Review ArticleClinical StudiesR

Prediction of Response in Cancer Immunotherapy

DAINIUS CHARACIEJUS, JOHN J.L. JACOBS, VITA PAŠUKONIENĖ, NIJOLĖ KAZLAUSKAITĖ, VITA DANILEVIČIŪTĖ, MYKOLAS MAURICAS and WILLEM DEN OTTER
Anticancer Research February 2011, 31 (2) 639-647;

Abstract

This review focuses on the relationship between pre-treatment immune parameter values and outcome of immunotherapy of cancer patients. The evidence presented in this review suggests that there is a relationship between pre-treatment immune parameter values and survival of cancer patients treated with immunotherapy. Tumour-infiltrating immune cells may have a predictive value for immunotherapy, but predictive power might be obtained from peripheral blood leukocytes. Use of peripheral blood may be preferable due to the convenience of collection and analysis compared to using tumour-infiltrating cells. In vivo numbers of cells of the immune system correlate better with clinical outcome than their functional activity ex vivo. This suggests that immunological antitumour mechanisms in vivo are not always related to generally accepted functional parameters of lymphocytes, such as cytotoxicity or cytokine production, ex vivo. The proliferative status of CD8+ T lymphocytes seems promising for prediction of response in cancer immunotherapy.

The effect of chemotherapy or so called ‘targeted’ antitumour therapy of the most common cancers is still quite modest, with a survival improvement of a few weeks or months (1). Increased understanding of the immune system and the increasing recognition of the importance of host-tumour interaction may lead to developing new immunotherapeutic strategies and improvements in therapeutic choices for patients with cancer (2).

Accumulating evidence demonstrates that the length of the survival of cancer patients may depend on the antitumour immune response of the host. In various tumour types, including lung, urothelial, renal cell, esophageal, colorectal, ovarian and endometrial cancer, and malignant pleural mesothelioma (3-11), the presence of CD8+ T-cells within a tumour is correlated with longer survival. The presence of proliferating CD8+ lymphocytes is important for the control of disease (3). Some studies suggest that quantities and proportions of T (mainly CD8+) lymphocyte subsets in peripheral blood may also be related to survival of cancer patients (12-14). These data also show that antitumour immune responses in cancer patients are not uniform: in some patients, the immune system is capable of controlling the disease to a greater extent than in others.

Cancer immunotherapy is a rapidly expanding area of research and clinical practice. Cytokines, monoclonal antibodies, vaccines and adoptive cell immunotherapy are increasingly being studied in trials and used in clinical practice. Given the variable extent of antitumour immune reactivity in different patients, the question arises whether effectiveness of a given immunotherapeutic approach may depend on a pre-existing immune state of a patient.

Prognostic markers are baseline (pre-treatment) measurements that provide information about a patient's likely long-term outcome, either untreated or with standard treatment. Prognostic markers can be used to determine whether a patient requires any systemic treatment or any treatment beyond the standard treatment. Predictive markers are baseline measurements that indicate whether a patient is likely (or unlikely) to benefit from a specific drug or regimen (15). Molecular markers, gene expression profile in tumour cells and serum proteins may have a predictive value in cancer immunotherapy (16-19). Immunotherapy, by definition, involves immunological events. Therefore, it is logical to assume that immune parameters will eventually yield the necessary predictive indicators (20). In a number of studies, the monitoring of immune parameter values during immunotherapy was performed. Post-treatment variables, such as the height of rebound lymphocytosis, treatment-induced thrombocytopenia, development of autoimmune thyroiditis and vitiligo, and changes in absolute number and frequency of peripheral T-regulatory cells were found to correlate with the outcome of immunotherapy (21). The aim of the present paper is to review the relationship between pre-treatment immune parameter values and the outcome of immunotherapy. In some studies, the predictive significance of immune parameter values cannot be strictly separated from their prognostic significance. Thus, in some cases, the prognostic significance of immune parameter values will be also mentioned.

Prediction of Response to Bacillus Calmette-Guérin Immunotherapy

Intravesical instillation of bacillus Calmette-Guérin (BCG) was the first immunotherapy to demonstrate reproducible activity in cancer patients (22) and is regarded to be the most effective immunotherapy identified to date. Recent analyses confirm the long-lasting effect of treatment with intravesical BCG on recurrence and progression in high-risk bladder cancer patients. This treatment now is considered also in cases of indermediate-risk bladder tumours (23). However, approximately 30-40% of patients fail to respond to BCG immunotherapy.

Evidence has been accumulating for some time that immunological markers are predictive of the BCG response. Conversion of purified protein derivative (PPD) skin reaction from negative to positive, formation of granulomas in the bladder, and an increase in levels of urinary cytokines, interleukin-2 (IL-2) in particular, during or after treatment have been correlated with response (20). However, changes of immune parameter values during or after BCG administration do not help in selecting patients for this type of treatment and cannot be regarded as predictive.

Some evidence indicates that immune parameter values measured before treatment can correlate with therapeutic effects of BCG. In a recent study, Ayari et al. (24) showed that maintenance BCG (more than one cycle) was highly effective in patients with a low level of CD83+ tumour-infiltrating dendritic cells at time of resection, but BCG showed reduced efficacy in patients with a high level of CD83+ tumour-infiltrating dendritic cells. In the same patient population, a strong infiltration of CD68+ tumour-associated macrophages was associated with an increased risk of recurrence.

Thus, although studies on the relationship between pre-treatment immune parameter values and the outcome of BCG therapy of bladder carcinoma are relatively scarce, they suggest that the response to BCG therapy can be predicted.

Prediction of Response to Cytokine Therapy

Reproducible therapeutic activity of recombinant cytokines was demonstrated in some forms of cancer, including renal cell carcinoma and melanoma in the 1980s (25). Although the complete or partial response rate with cytokines is rather low, some long-lasting remissions are achieved (26-29). It is extremely important to find pre-treatment immune parameters that would predict prolongation of survival after cytokine therapy. Tumour-infiltrating immune cells and lymphocytes in peripheral blood have been studied in an attempt to find such predictive parameters.

Tumour-infiltrating immune cells. Håkansson et al. (30) observed a significantly longer time to progression and longer overall survival among metastatic melanoma patients with moderate to high numbers of CD4+ tumour-infiltrating lymphocytes compared to patients with low numbers of these cells before initiation of chemoimmunotherapy (cisplatin, dacarbazine, interferon (IFN)-α2b). In 85 patients with metastatic renal cell carcinoma, Donskov and von der Maase identified the presence of intratumoural neutrophils (>0 cells/mm2 tumour tissue), low intratumoural CD57+ cell count (<50 cells/mm2 tumour tissue), and high blood neutrophil count (>6.0×109/l) as independent poor prognostic factors for the outcome of IL-2-based immunotherapy (31). In a recent study, the same group established that long-term survival of IL-2-treated metastatic renal cell carcinoma patients was associated with low-baseline intratumoural FOXP3+ cells and a modest absolute rise in these cells during treatment. Achieving high numbers (>180 cells/μl) of on-treatment FOXP3+ intratumoural immune cells was associated with poor survival (32).

Increased tumour infiltration of mature (CD83+) dendritic cells predicted longer survival of metastatic renal cell carcinoma patients who received cytokine-based immunotherapy (IFN-α monotherapy or a combination of IFN-α, IL-2 and fluoro-pyrimidine). Interestingly, expression of S100 protein on intratumoural dendritic cells was associated with tumour size reduction after therapy, but not with survival (33).

Leukocytes in peripheral blood. Fumagalli et al. (34) have found that the pre-treatment lymphocyte count in peripheral blood is a prognostic factor for overall survival in metastatic renal cancer patients treated with subcutaneous IL-2 immunotherapy. The prognostic/predictive significance of the peripheral blood lymphocyte count for overall survival was independent of tumour response and of major prognostic clinical characteristics (performance status, time from primary diagnosis and number of metastatic sites).

High pre-treatment counts of neutrophils and total leukocytes in blood were confirmed as independent prognostic factors for short overall survival in stage IV melanoma patients undergoing IL-2-based immunotherapy (35).

A panel of lymphocyte subsets (CD3+, CD19+, CD16+56+, CD4+, CD8+, CD4+CD45ROhigh and CD8highCD57+) was analysed by this group in peripheral blood of 85 advanced renal cell carcinoma patients in an attempt to find immunological parameters with the predictive significance for survival after treatment with IFN-α2b (14). In addition to absolute counts, the percentage of CD8highCD57+ lymphocytes in the CD8+ subset, the percentage of CD4+CD45ROhigh lymphocytes in the CD4+ subset and the CD4+/CD8+ ratio were analysed. The only lymphocyte subset that significantly correlated with survival of IFN-α2b treated advanced renal cell carcinoma patients was CD8highCD57+ lymphocytes. CD8highCD57+ lymphocytes can be considered to be T cells, whereas CD8lowCD57+ lymphocytes may contain NK cells (36, 37). Non-treated patients with ≥30% CD8highCD57+ lymphocytes in the CD8+ subset had a shorter survival time than patients with <30% CD8highCD57+ lymphocytes in the CD8+ subset. Thus, results of this study suggest a negative role for CD8highCD57+ lymphocytes in the natural course of advanced renal cell carcinoma. Treatment with IFN-α2b increased overall survival only in the subgroup of patients with ≥30% CD8highCD57+ lymphocytes. Unpublished observations from the current authors suggest that numbers of CD8highCD57+ lymphocytes decrease in these patients during therapy with IFN-α2b.

Remarkable differences in survival, depending on pre-treatment levels of CD8highCD57+ lymphocytes in peripheral blood, were observed by the current authors in 16 melanoma patients treated with adjuvant IFN-α2b (38). Patients with <23% CD8highCD57+ lymphocytes in the CD8+ subset prior to treatment survived considerably longer than patients with >23% CD8highCD57+ lymphocytes. Lower pre-treatment values (<23%) of these lymphocytes tended to increase, whereas higher values (>23%) tended to decrease during the first few months of treatment with IFN-α2b. Thus, in contrast to a negative role of CD8highCD57+ lymphocytes in advanced renal cell carcinoma, these lymphocytes seem to play a positive role in adjuvant treatment with IFN-α2b of melanoma. These data are in line with other published reports suggesting that an increase in CD8+CD57+ T lymphocytes is associated with prolonged survival of melanoma patients after vaccination therapy (39, 40).

The predictive and/or prognostic significance of peripheral blood CD8highCD57+ lymphocytes was also shown in patients with non-muscle invasive bladder carcinoma receiving intravesical instillations of IL-2 after transurethral resection of tumours. High pre-treatment levels of CD8highCD57+ lymphocytes in peripheral blood independently predicted short recurrence-free interval in these patients (41).

The above data on cytokine therapy indicate that both tumour-infiltrating cells and peripheral blood lymphocytes may have a predictive value. Peripheral blood represents only about 2% of the total lymphocyte pool in the human body.

Thus, on the one hand, it may seem unlikely that the lymphocytes of this small compartment are representative of the other 98% lymphocytes in all organs, and a malignant tumour. On the other hand, it has been estimated that roughly 500×109 lymphocytes travel through the blood each day. This is about the same number as the number of lymphocytes within the human body. Since most lymphoid and non-lymphoid organs are included in the migration/circulation routes of lymphocytes, alterations in the lymphocyte composition within these organs might be detected by studying lymphocyte subsets in the blood (42, 43).

Thus, there are reports suggesting a relationship between pre-treatment immune parameter values and the outcome of cytokine therapy. Unfortunately, in the majority of studies, the phenotype of immune cells with possible predictive value has not been determined (e.g. total leukocytes, total lymphocytes, total neutrophils), or has been determined by just one marker (e.g. CD4+ lymphocytes, CD57+ cells, FOXP3+ cells). This is obviously insufficient for the precise determination of a cell type. In only a few studies were at least two markers used for determination of the phenotype of immune cells. These studies suggest that the immune cell types predicting the response in cytokine therapy of cancer are subsets of CD8+ T lymphocytes (Table I).

Prediction of Response to Monoclonal Antibody Therapy

Monoclonal antibodies probably are the most widely used cancer immunotherapeutics at present (44). Monoclonal antibodies that act directly on tumour cells are ‘targeted’ against an antigen expressed on tumour cells. Unexpectedly, responses are achieved only in a proportion of patients whose tumours express an antigen, against which the monoclonal antibody is targeted (45-47). This indicates that better predictors of response to monoclonal antibody therapy are needed.

Polymorphisms of receptors for immunoglobulin G (FcγRs). It has been suggested that immune mechanisms, including antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) may be involved in the killing of tumour cells by monoclonal antibodies. In ADCC, the antibody binds to tumour cells and then is engaged by effector cells, such as NK cells or macrophages, via their FcγRs. FcγRIIIa (CD16) is expressed on both NK cells and macrophages, whereas FcγRIIa and FcγRIIb (CD32) are found only on macrophages (48). Based on the evidence that properties of FcγRIIIa depend on the FCGR3A gene dimorphism with either a phenylalanine (F) or a valine (V) at amino acid position 158, Cartron et al. (49) evaluated the relationship between FCGR3A genotype and response to rituximab in 49 patients with untreated non-Hodgkin follicular lymphoma. The objective response rates at two months and at one year were 100% and 90%, respectively, in FCGR3A-158 V homozygous patients compared with 67% and 51%, respectively, in FCGR3A-158 F carriers. Disappearance of the BCL2-JH gene rearrangement (used for monitoring of molecular response) was observed in both peripheral blood and marrow at one year in 5 out of 6 homozygous FCGR3A-158 V patients compared with 5 of 17 of FCGR3A-158 F carriers. The observation of Cartron et al. (49) was confirmed in the study of Weng and Levy (48) including 87 follicular lymphoma patients who received rituximab as second-line treatment. Furthermore, these authors determined the association between FcγRIIa 131 histidine (H)/arginine (R) polymorphism and rituximab response. Both FcγRIIIa 158 V/V and FcγRIIa 131 H/H genotypes were independently associated with the response rate and progression-free survival in patients with follicular lymphoma (46). However, neither FcγRIIIa nor FcγRIIa polymorphisms predicted response to rituximab in B-cell chronic lymphocytic leukaemia (45).

View this table:
Table I.

Summary of data indicating predictive significance of pre-treatment immune parameters in cancer immunotherapy.

The significance FcγRIIIa and FcγRIIa polymorphisms was reported for other humanized IgG1 antibodies, namely trastuzumab and cetuximab. FcγRIIIa 158 V/V genotype (and to lower extent of FcγRIIa 131 H/H genotype) appeared to be predictive for objective response rate and progression-free survival in HER-2/neu-positive metastatic breast cancer patients treated with trastuzumab-based therapy. The ADCC analysis showed that peripheral blood mononuclear cells of FcγRIIIa 158 V/V genotype had a significantly higher trastuzumab-mediated cytotoxicity than cells harbouring 158 V/F and 158 F/F genotypes (50). Metastatic colorectal cancer patients with FcγRIIa 131 H/H and/or FcγIIIa-158 V/V genotypes had longer progression-free survival after treatment with cetuximab plus irinotecan than 131 R and 158 F carriers (5.5 versus 3.0 months) (51).

The results described above indicate that polymorphisms of FcγRs can predict the response to monoclonal antibody therapy. However, there are some data against the involvement of ADCC in the clinical effect of antitumour monoclonal antibodies. No correlation was found between the in vitro susceptibility of pre-treatment tumour cells to rituximab-mediated ADCC and the clinical outcome in patients with follicular lymphoma (48).

FcγRs are also important in antibody-mediated antigen uptake and cross-presentation of tumour antigens by dendritic cells to stimulate specific CD4+ and CD8+ T lymphocyte response (52, 53). CD4+ and CD8+ T lymphocytes are considered to be the key players in antitumour immune responses. Considering the potential influence of FcγR polymorphisms on the priming of cellular immunity, it cannot be excluded that the predictive value of FcγR phenotypes is independent of ADCC, but depends on cellular immunity. Indeed, some data suggest that T lymphocytes may be involved in the therapeutic effect of monoclonal antibodies. Decrease in regulatory T-cell numbers (54, 55), increase in Th17 cell numbers (55) in the peripheral blood and augmentation of HER-2/neu-specific CD4 T-cell responses (56) have been reported in advanced breast cancer patients receiving trastuzumab therapy. Therefore, studies aimed at finding a relationship between pre-treatment T lymphocyte parameters and clinical outcome in monoclonal antibody therapy would be of interest.

Prediction of Response to Vaccination Therapy

Using cancer vaccines to harness the power of the cancer patient's own immune system is a highly attractive and innovative approach to cancer management (57). However, many cancer vaccines have shown little evidence of clinical antitumour effect so far. In contrast, dendritic cell-based vaccines are associated with a low (approximately 14%) but consistent clinical response rate (58). To date, most efforts have been directed toward the immune monitoring of antigen-specific T-cells within peripheral blood of vaccinated cancer patients. Indeed, induction of tetramer-specific T-cells in melanoma patients after vaccination correlates with progression-free survival (59). Studies relating the survival of vaccine-treated cancer patients with pre-treatment immune parameter values are scarce. In one study (60), patients with several advanced malignancies (various primary sites) were divided into three groups according to their survival time after an intravenous injection of tumour cell-pulsed monocyte-derived dendritic cells and activated lymphocytes. It was shown that the percentage of regulatory T-cells (CD4+CD25high) among total CD4+ T-cells in peripheral blood before the therapy was significantly lower in long-survival patients than in the short-survival patients. In another study, 14 colorectal cancer patients were treated with dendritic cells loaded with lysate from a cloned and selected melanoma cell line enriched in expression of cancer/testis (MAGE) antigens. Eleven out of the fourteen colorectal cancer patients were considered MAGE-positive. Although no complete or partial responses were observed in this study, four of the fourteen patients achieved stable disease. Pre-treatment levels of plasma IL-6 were lower in patients with stable disease compared to patients with disease progression (61).

Studies on the relationship between pre-treatment immune parameter values and the outcome of vaccination therapy of cancer patients are scarce. However, the existing evidence suggests that pre-treatment immune parameters may predict a response to vaccination therapy. Further studies in this field are needed.

Prediction of Response to Adoptive Cell Immunotherapy

Probably the earliest form of adoptive T-cell immunotherapy has been allogeneic hematopoietic cell transplantation. The assumption that donor T-cells exert a graft-versus-tumour effect was corroborated by demonstration of therapeutic effects of donor lymphocyte infusions (DLI) (62). The greatest success with DLI has been seen in chronic myelogenous leukaemia, where durable remissions are achieved in 70% to 80% of patients. DLI are less successful in other haematological malignancies, including acute lymphocytic leukaemia, multiple myeloma, chronic lymphocytic leukaemia and indolent non-Hodgkin's lymphoma (63).

Tumour-infiltrating lymphocytes or peripheral lymphocytes repeatedly stimulated in vitro with autologous melanoma cells often demonstrate in vitro recognition of melanoma cells based on assays of lysis or cytokine secretion. The techniques have been developed to grow large numbers of anti tumour lymphocytes using tumor-infiltrating lymphocytes. It was found that lymphodepletion in metastatic melanoma patients prior to transfer of expanded autologous tumor-infiltrating lymphocytes results in relatively high objective response rates ranging between 49% and 72% (64). Possible explanations for the effect of lymphodepletion include elimination of autologous regulatory T-cells and elimination of competition for homeostatic cytokines, such as IL-7 and IL-15, that are vital for T-cell survival. Thus, levels of autologous regulatory T cells, IL-7 and/or IL-15 might predict a response to adoptive cell immunotherapy. However, the data to prove this are not yet available.

Regarding the transferred lymphocytes, the anti tumour response correlated with the mean telomere length of the cells infused and with the number of CD8+CD27+ T cells infused (64). Telomere length is related to the capacity for cell division, even though this relationship in lymphocytes may be rather complex (65). Expression of CD27 antigen correlates with resistance to apoptosis, IL-2 production, and proliferative potential of CD8+ T lymphocytes (66). These data suggest that proliferative potential of the infused CD8+ T lymphocytes can predict the success of the treatment.

Conclusions and Future Prospects

Prediction of response in cancer immunotherapy is promising for two main reasons. First, the success of immunotherapy may be increased by administering this type of treatment only to patients with biomarkers that correlate with positive therapeutic effects. Avoiding immunotherapy for patients with biomarkers that predict negative therapeutic effects becomes of utmost importance due to the possibility of the cancer-promoting effect of immunotherapy (67). Second, establishing the relationship between pre-treatment parameter values of the patient's immune system and the outcome of immunotherapy may help understand the therapeutic mechanisms induced by immune manipulation.

The evidence presented in this review strongly suggests that there is a relationship between pre-treatment immune parameter values and outcome of immunotherapy of cancer patients. A summary of data indicating the predictive significance of pre-treatment immune parameter values in cancer immunotherapy is presented in Table I. The reviewed literature suggests that tumour-infiltrating cells of the immune system may have predictive value for immunotherapy, but probably they do not have an advantage over cells circulating in peripheral blood. Use of peripheral blood may be preferable due to the greater convenience of collection and analysis compared to using tumour-infiltrating cells.

The most important question to answer is, which of the immune parameter(s) is (are) the most promising for future studies of predictive biomarkers? Several lines of evidence suggest that subsets of CD8+ T lymphocytes deserve special attention in search of predictive markers. CD8+ T lymphocytes are well-documented effectors of tumour immunity (68). CD8+, but not CD4+, T-cells are required for the maintenance of tumour dormancy in an experimental mouse model (69). There is ample evidence for the prognostic significance of CD8+ T lymphocytes in cancer patients (reviewed in the introduction). It is therefore logical to assume that numbers of CD8+ lymphocytes may reflect antitumour immune reactivity of the cancer patient and predict the response to immunotherapy. Indeed, predictive significance of CD8+ T lymphocytes has been demonstrated in cytokine therapy and in adoptive cell immunotherapy of cancer. Predictive significance of CD8+ T lymphocytes in monoclonal antibody therapy, vaccination therapy, and in BCG immunotherapy still awaits investigation.

On the other hand, there is increasing evidence that markers on CD8+ T lymphocytes may serve as measure of functional immune deficiency in patients with various diseases including cancer (70). Interestingly, the frequency of CD8+ lymphocyte subsets (CD8+CD28−), but not of CD4+ lymphocyte subsets, predicted the responsiveness to influenza vaccination in elderly individuals (71).

Most of the evidence reviewed in this article concerns the in vivo numbers of cells of the immune system. We were not able to find any published data on the relationship between pre-treatment functional characteristics of immune cells ex vivo and the outcome of immunotherapy. Antitumour immune mechanisms in vivo may be more complex than mechanisms detected by lymphocyte functional studies ex vivo, such as cytokine production or cytotoxicity. Indeed, a dichotomy between in vitro CD8+ T cell responses and in vivo antitumour immunity of these cells has been shown in an experimental mouse model (72, 73). Furthermore, presence in tumour biopsies of cytotoxic T-lymphocytes, as determined by the percentage of CD3+ lymphocytes with granzyme B expression, was unexpectedly found to correlate with reduced overall survival in patients suffering from Hodgkin's disease or non-Hodgkin's lymphomas (74).

Several reports suggest that expansion of CD8+ lymphocytes (mainly as CD8+CD57+ subset) in cancer patients is a prerequisite for the successful control of the disease (12, 13, 39, 40). These reports underscore the predictive importance of the proliferative potential of CD8+ lymphocytes. Indeed, the proliferative potential of the infused lymphocytes is critical to the success of adoptive cell immunotherapy (64). It is interesting to note that in adult humans, CD8+ T-cells have a more than two fold faster doubling time than CD4+ cells (75). Thus, markers of the replicative status of CD8+ T lymphocytes, such as CD57 and/or CD27, seem promising in studies of predictive biomarkers in cancer immunotherapy. Hopefully, the results of these studies will allow identification of cancer patients who would benefit most from immunotherapy.

Acknowledgements

The study was supported by a grant LIG-23/2010 from Research Council of Lithuania. JJLJ acknowledges a grant from SNFK, Amsterdam, the Netherlands.

  • Received December 30, 2010.
  • Revision received January 25, 2011.
  • Accepted January 25, 2011.

References

  1. ↵
    1. Stewart DJ,
    2. Kurzrock R
    : Cancer: the road to Amiens. J Clin Oncol 27: 328-333, 2009.
    OpenUrlFREE Full Text
  2. ↵
    1. Marshall JL
    : Time to shift the focus of the war: it is not all about the enemy. J Clin Oncol 27: 168-169, 2009.
    OpenUrlFREE Full Text
  3. ↵
    1. Nakano O,
    2. Sato M,
    3. Naito Y,
    4. Suzuki K,
    5. Orikasa S,
    6. Aizawa M,
    7. Suzuki Y,
    8. Shintaku I,
    9. Nagura H,
    10. Ohtani H
    : Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res 61: 5132-5136, 2001.
    OpenUrlAbstract/FREE Full Text
    1. Schumacher K,
    2. Haensch W,
    3. Röefzaad C,
    4. Schlag PM
    : Prognostic significance of activated CD8(+) T-cell infiltrations within esophageal carcinomas. Cancer Res 61: 3932-3936, 2001.
    OpenUrlAbstract/FREE Full Text
    1. Ohtani H
    : Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human colorectal cancer. Cancer Immun 7: 4, 2007.
    OpenUrlPubMed
    1. Sharma P,
    2. Shen Y,
    3. Wen S,
    4. Yamada S,
    5. Jungbluth AA,
    6. Gnjatic S,
    7. Bajorin DF,
    8. Reuter VE,
    9. Herr H,
    10. Old LJ,
    11. Sato E
    : CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc Natl Acad Sci USA 104: 3967-3972, 2007.
    OpenUrlAbstract/FREE Full Text
    1. Kawai O,
    2. Ishii G,
    3. Kubota K,
    4. Murata Y,
    5. Naito Y,
    6. Mizuno T,
    7. Aokage K,
    8. Saijo N,
    9. Nishiwaki Y,
    10. Gemma A,
    11. Kudoh S,
    12. Ochiai A
    : Predominant infiltration of macrophages and CD8(+) T-cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer. Cancer 113: 1387-1395, 2008.
    OpenUrlCrossRefPubMed
    1. de Jong RA,
    2. Leffers N,
    3. Boezen HM,
    4. ten Hoor KA,
    5. van der Zee AG,
    6. Hollema H,
    7. Nijman HW
    : Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and II endometrial cancer. Gynecol Oncol 114: 105-110, 2009.
    OpenUrlCrossRefPubMed
    1. Leffers N,
    2. Gooden MJ,
    3. de Jong RA,
    4. Hoogeboom BN,
    5. ten Hoor KA,
    6. Hollema H,
    7. Boezen HM,
    8. van der Zee AG,
    9. Daemen T,
    10. Nijman HW
    : Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 58: 449-459, 2009.
    OpenUrlCrossRefPubMed
    1. Suzuki H,
    2. Chikazawa N,
    3. Tasaka T,
    4. Wada J,
    5. Yamasaki A,
    6. Kitaura Y,
    7. Sozaki M,
    8. Tanaka M,
    9. Onishi H,
    10. Morisaki T,
    11. Katano M
    : Intratumoral CD8(+) T/FOXP3 (+) cell ratio is a predictive marker for survival in patients with colorectal cancer. Cancer Immunol Immunother 59: 653-661, 2010.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Yamada N,
    2. Oizumi S,
    3. Kikuchi E,
    4. Shinagawa N,
    5. Konishi-Sakakibara J,
    6. Ishimine A,
    7. Aoe K,
    8. Gemba K,
    9. Kishimoto T,
    10. Torigoe T,
    11. Nishimura M
    : CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection. Cancer Immunol Immunother 59: 1543-1549, 2010.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Dolstra H,
    2. Preijers F,
    3. Van de Wiel-van Kemenade E,
    4. Schattenberg A,
    5. Galama J,
    6. de Witte T
    : Expansion of CD8+CD57+ T-cells after allogeneic BMT is related with a low incidence of relapse and with cytomegalovirus infection. Br J Haematol 90: 300-307, 1995.
    OpenUrlCrossRefPubMed
  13. ↵
    1. Sze DM,
    2. Brown RD,
    3. Yuen E,
    4. Gibson J,
    5. Ho J,
    6. Raitakari M,
    7. Basten A,
    8. Joshua DE,
    9. Fazekas de St Groth B
    : Clonal cytotoxic T-cells in myeloma. Leuk Lymphoma 44: 1667-1674, 2003.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Characiejus D,
    2. Pasukoniene V,
    3. Kazlauskaite N,
    4. Valuckas KP,
    5. Petraitis T,
    6. Mauricas M,
    7. Den Otter W
    : Predictive value of CD8highCD57+ lymphocyte subset in interferon therapy of patients with renal cell carcinoma. Anticancer Res 22: 3679-3683, 2002.
    OpenUrlPubMed
  15. ↵
    1. Simon R
    : Moving from correlative science to predictive oncology. EPMA J 1: 377-387, 2010.
    OpenUrlPubMed
  16. ↵
    1. Sabatino M,
    2. Kim-Schulze S,
    3. Panelli MC,
    4. Stroncek D,
    5. Wang E,
    6. Taback B,
    7. Kim DW,
    8. Deraffele G,
    9. Pos Z,
    10. Marincola FM,
    11. Kaufman HL
    : Serum vascular endothelial growth factor and fibronectin predict clinical response to high-dose interleukin-2 therapy. J Clin Oncol 27: 2645-2652, 2009.
    OpenUrlAbstract/FREE Full Text
    1. Dudek AZ,
    2. Yee RT,
    3. Manivel JC,
    4. Isaksson R,
    5. Yee HO
    : Carbonic anhydrase IX expression is associated with improved outcome of high-dose interleukin-2 therapy for metastatic renal cell carcinoma. Anticancer Res 30: 987-992, 2010.
    OpenUrlAbstract/FREE Full Text
    1. Gajewski TF,
    2. Louahed J,
    3. Brichard VG
    : Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J 16: 399-403, 2010.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Kim YJ,
    2. Ha YS,
    3. Kim SK,
    4. Yoon HY,
    5. Lym MS,
    6. Kim MJ,
    7. Moon SK,
    8. Choi YH,
    9. Kim WJ
    : Gene signatures for the prediction of response to bacillus Calmette-Guerin immunotherapy in primary pT1 bladder cancers. Clin Cancer Res 16: 2131-2137, 2010.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Saint F,
    2. Salomon L,
    3. Quintela R,
    4. Cicco A,
    5. Hoznek A,
    6. Abbou CC,
    7. Chopin DK
    : Do prognostic parameters of remission versus relapse after bacillus Calmette-Guérin (BCG) immunotherapy exist? Analysis of a quarter century of literature. Eur Urol 43: 351-360, 2003.
    OpenUrlCrossRefPubMed
  21. ↵
    1. Kirkwood JM,
    2. Tarhini AA
    : Biomarkers of therapeutic response in melanoma and renal cell carcinoma: potential inroads to improved immunotherapy. J Clin Oncol 27: 2583-2585, 2009.
    OpenUrlFREE Full Text
  22. ↵
    1. Morales A,
    2. Eidinger D,
    3. Bruce AW
    : Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol 116: 180-183, 1976.
    OpenUrlCrossRefPubMed
  23. ↵
    1. Böhle A
    : Bladder cancer: meta-analysis of BCG versus mitomycin C - A deeper insight? Nat Rev Urol 7: 8-10, 2010.
    OpenUrlPubMed
  24. ↵
    1. Ayari C,
    2. LaRue H,
    3. Hovington H,
    4. Decobert M,
    5. Harel F,
    6. Bergeron A,
    7. Têtu B,
    8. Lacombe L,
    9. Fradet Y
    : Bladder tumor-infiltrating mature dendritic cells and macrophages as predictors of response to bacillus Calmette-Guérin immunotherapy. Eur Urol 55: 1386-1395, 2009.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Rosenberg SA,
    2. Lotze MT,
    3. Muul LM,
    4. Leitman S,
    5. Chang AE,
    6. Ettinghausen SE,
    7. Matory YL,
    8. Skibber JM,
    9. Shiloni E,
    10. Vetto JT,
    11. Seipp CA,
    12. Simpson C,
    13. Reichert CM
    : Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313: 1485-1492, 1985.
    OpenUrlCrossRefPubMed
  26. ↵
    1. Den Otter W,
    2. Dobrowolski Z,
    3. Bugajski A,
    4. Papla B,
    5. Van Der Meijden AP,
    6. Koten JW,
    7. Boon TA,
    8. Siedlar M,
    9. Zembala M
    : Intravesical interleukin-2 in T1 papillary bladder carcinoma: regression of marker lesion in 8 of 10 patients. J Urol 159: 1183-1186, 1998.
    OpenUrlCrossRefPubMed
    1. Jacobs JJL,
    2. Hordijk GJ,
    3. Jürgenliemk-Schulz IM,
    4. Terhaard CH,
    5. Koten JW,
    6. Battermann JJ,
    7. Den Otter W
    : Treatment of stage III-IV nasopharyngeal carcinomas by external beam irradiation and local low doses of IL-2. Cancer Immunol Immunother 54: 792-798, 2005.
    OpenUrlCrossRefPubMed
    1. Den Otter W,
    2. Jacobs JJL,
    3. Battermann JJ,
    4. Hordijk GJ,
    5. Krastev Z,
    6. Moiseeva EV,
    7. Stewart RJE,
    8. Ziekman PGPM,
    9. Koten JW
    : Local therapy of cancer with free IL-2. Cancer Immunol Immunother 57: 931-950, 2008.
    OpenUrlCrossRefPubMed
  29. ↵
    1. McDermott DF,
    2. Atkins MB
    : Immunotherapy of metastatic renal cell carcinoma. Cancer J 14: 320-324, 2008.
    OpenUrlPubMed
  30. ↵
    1. Håkansson A,
    2. Gustafsson B,
    3. Krysander L,
    4. Hjelmqvist B,
    5. Rettrup B,
    6. Håkansson L
    : Biochemotherapy of metastatic malignant melanoma. Predictive value of tumour-infiltrating lymphocytes. Br J Cancer 85: 1871-1877, 2001.
    OpenUrlCrossRefPubMed
  31. ↵
    1. Donskov F,
    2. von der Maase H
    : Impact of immune parameters on long-term survival in metastatic renal cell carcinoma. J Clin Oncol 24: 1997-2005, 2006.
    OpenUrlAbstract/FREE Full Text
  32. ↵
    1. Jensen HK,
    2. Donskov F,
    3. Nordsmark M,
    4. Marcussen N,
    5. von der Maase H
    : Increased intratumoral FOXP3-positive regulatory immune cells during interleukin-2 treatment in metastatic renal cell carcinoma. Clin Cancer Res 15: 1052-1058, 2009.
    OpenUrlAbstract/FREE Full Text
  33. ↵
    1. Kobayashi M,
    2. Suzuki K,
    3. Yashi M,
    4. Yuzawa M,
    5. Takayashiki N,
    6. Morita T
    : Tumor-infiltrating dendritic cells predict treatment response to immmunotherapy in patients with metastatic renal cell carcinoma. Anticancer Res 27: 1137-1141, 2007.
    OpenUrlAbstract/FREE Full Text
  34. ↵
    1. Fumagalli LA,
    2. Vinke J,
    3. Hoff W,
    4. Ypma E,
    5. Brivio F,
    6. Nespoli A
    : Lymphocyte counts independently predict overall survival in advanced cancer patients: a biomarker for IL-2 immunotherapy. J Immunother 26: 394-402, 2003.
    OpenUrlCrossRefPubMed
  35. ↵
    1. Schmidt H,
    2. Suciu S,
    3. Punt CJ,
    4. Gore M,
    5. Kruit W,
    6. Patel P,
    7. Lienard D,
    8. von der Maase H,
    9. Eggermont AM,
    10. Keilholz U
    : Pretreatment levels of peripheral neutrophils and leukocytes as independent predictors of overall survival in patients with American Joint Committee on Cancer Stage IV Melanoma: results of the EORTC 18951 Biochemotherapy Trial. J Clin Oncol 25: 1562-1569, 2007.
    OpenUrlAbstract/FREE Full Text
  36. ↵
    1. Morley JK,
    2. Batliwalla FM,
    3. Hingorani R,
    4. Gregersen PK
    : Oligoclonal CD8+ T-cells are preferentially expanded in the CD57+ subset. J Immunol 154: 6182-6190, 1995.
    OpenUrlAbstract
  37. ↵
    1. Wang ECY,
    2. Moss PAH,
    3. Frodsham P,
    4. Lehner PJ,
    5. Bell JI,
    6. Borysiewicz LK
    : CD8highCD57+ lymphocytes in normal, healthy individuals are oligoclonal and respond to human cytomegalovirus. J Immunol 155: 5046-5056, 1995.
    OpenUrlAbstract
  38. ↵
    1. Characiejus D,
    2. Pasukoniene V,
    3. Jonusauskaite R,
    4. Kazlauskaite N,
    5. Aleknavicius E,
    6. Mauricas M,
    7. Den Otter W
    : Peripheral blood CD8highCD57+ lymphocyte levels may predict outcome in melanoma patients treated with adjuvant interferon-alpha. Anticancer Res 28: 1139-1142, 2008.
    OpenUrlAbstract/FREE Full Text
  39. ↵
    1. Elliott GT,
    2. McLeod RA,
    3. Perez J,
    4. Von Eschen KB
    : Interim results of a phase II multicenter clinical trial evaluating the activity of a therapeutic allogeneic melanoma vaccine (theraccine) in the treatment of disseminated malignant melanoma. Semin Surg Oncol 9: 264-272, 1993.
    OpenUrlPubMed
  40. ↵
    1. Batliwalla FM,
    2. Bateman BA,
    3. Serrano D,
    4. Murray D,
    5. Macphail S,
    6. Maino VC,
    7. Ansel JC,
    8. Gregersen PK,
    9. Armstrong CA
    : A 15-year follow-up of AJCC stage III malignant melanoma patients treated postsurgically with Newcastle disease virus (NDV) oncolysate and determination of alterations in the CD8 T-cell repertoire. Mol Med 4: 783-794, 1998.
    OpenUrlPubMed
  41. ↵
    1. Characiejus D,
    2. Pasukoniene V,
    3. Jacobs JJL,
    4. Eidukevicius R,
    5. Jankevicius F,
    6. Dobrovolskiene N,
    7. Mauricas M,
    8. Van Moorselaar RJA,
    9. Den Otter W
    : Prognostic significance of peripheral blood CD8highCD57+ lymphocytes in bladder carcinoma patients after intravesical IL-2. Anticancer Res 31: 699-704, 2011.
    OpenUrlAbstract/FREE Full Text
  42. ↵
    1. Westermann J,
    2. Pabst R
    : Lymphocyte subsets in the blood: A diagnostic window on the lymphoid system? Immunol Today 11: 406-410, 1990.
    OpenUrlCrossRefPubMed
  43. ↵
    1. Blum KS,
    2. Pabst R
    : Lymphocyte numbers and subsets in the human blood. Do they mirror the situation in all organs? Immunol Lett 108: 45-51, 2007.
    OpenUrlCrossRefPubMed
  44. ↵
    1. Reichert JM
    : Monoclonal antibodies as innovative therapeutics. Curr Pharm Biotechnol 9: 423-430, 2008.
    OpenUrlCrossRefPubMed
  45. ↵
    1. Farag SS,
    2. Flinn IW,
    3. Modali R,
    4. Lehman TA,
    5. Young D,
    6. Byrd JC
    : Fc gamma RIIIa and Fc gamma RIIa polymorphisms do not predict response to rituximab in B-cell chronic lymphocytic leukemia. Blood 103: 1472-1474, 2004.
    OpenUrlAbstract/FREE Full Text
  46. ↵
    1. O'Donovan N,
    2. Crown J
    : EGFR and HER-2 antagonists in breast cancer. Anticancer Res 27: 1285-1294, 2007.
    OpenUrlAbstract/FREE Full Text
  47. ↵
    1. Lièvre A,
    2. Bachet JB,
    3. Boige V,
    4. Cayre A,
    5. Le Corre D,
    6. Buc E,
    7. Ychou M,
    8. Bouché O,
    9. Landi B,
    10. Louvet C,
    11. André T,
    12. Bibeau F,
    13. Diebold MD,
    14. Rougier P,
    15. Ducreux M,
    16. Tomasic G,
    17. Emile JF,
    18. Penault-Llorca F,
    19. Laurent-Puig P
    : KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 26: 374-379, 2008.
    OpenUrlAbstract/FREE Full Text
  48. ↵
    1. Weng WK,
    2. Levy R
    : Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 21: 3940-3947, 2003.
    OpenUrlAbstract/FREE Full Text
  49. ↵
    1. Cartron G,
    2. Dacheux L,
    3. Salles G,
    4. Solal-Celigny P,
    5. Bardos P,
    6. Colombat P,
    7. Watier H
    : Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcγRIIIa gene. Blood 99: 754-758, 2002.
    OpenUrlAbstract/FREE Full Text
  50. ↵
    1. Musolino A,
    2. Naldi N,
    3. Bortesi B,
    4. Pezzuolo D,
    5. Capelletti M,
    6. Missale G,
    7. Laccabue D,
    8. Zerbini A,
    9. Camisa R,
    10. Bisagni G,
    11. Neri TM,
    12. Ardizzoni A
    : Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol 26: 1789-1796, 2008.
    OpenUrlAbstract/FREE Full Text
  51. ↵
    1. Bibeau F,
    2. Lopez-Crapez E,
    3. Di Fiore F,
    4. Thezenas S,
    5. Ychou M,
    6. Blanchard F,
    7. Lamy A,
    8. Penault-Llorca F,
    9. Frébourg T,
    10. Michel P,
    11. Sabourin JC,
    12. Boissière-Michot F
    : Impact of FcγRIIa-FcγRIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol 27: 1122-1129, 2009.
    OpenUrlAbstract/FREE Full Text
  52. ↵
    1. Amigorena S
    : Fc gamma receptors and cross-presentation in dendritic cells. J Exp Med 195: F1-3, 2002.
    OpenUrlFREE Full Text
  53. ↵
    1. Akiyama K,
    2. Ebihara S,
    3. Yada A,
    4. Matsumura K,
    5. Aiba S,
    6. Nukiwa T,
    7. Takai T
    : Targeting apoptotic tumor cells to Fc gamma R provides efficient and versatile vaccination against tumors by dendritic cells. J Immunol 170: 1641-1648, 2003.
    OpenUrlAbstract/FREE Full Text
  54. ↵
    1. Perez SA,
    2. Karamouzis MV,
    3. Skarlos DV,
    4. Ardavanis A,
    5. Sotiriadou NN,
    6. Iliopoulou EG,
    7. Salagianni ML,
    8. Orphanos G,
    9. Baxevanis CN,
    10. Rigatos G,
    11. Papamichail M
    : CD4+CD25+ regulatory T-cell frequency in HER-2/neu (HER)-positive and HER-negative advanced-stage breast cancer patients. Clin Cancer Res 13: 2714-2721, 2007.
    OpenUrlAbstract/FREE Full Text
  55. ↵
    1. Horlock C,
    2. Stott B,
    3. Dyson PJ,
    4. Morishita M,
    5. Coombes RC,
    6. Savage P,
    7. Stebbing J
    : The effects of trastuzumab on the CD4+CD25+FoxP3+ and CD4+IL17A+ T-cell axis in patients with breast cancer. Br J Cancer 100: 1061-1067, 2009.
    OpenUrlCrossRefPubMed
  56. ↵
    1. Taylor C,
    2. Hershman D,
    3. Shah N,
    4. Suciu-Foca N,
    5. Petrylak DP,
    6. Taub R,
    7. Vahdat L,
    8. Cheng B,
    9. Pegram M,
    10. Knutson KL,
    11. Clynes R
    : Augmented HER-2 specific immunity during treatment with trastuzumab and chemotherapy. Clin Cancer Res 13: 5133-5143, 2007.
    OpenUrlAbstract/FREE Full Text
  57. ↵
    1. Emens LA
    : Cancer vaccines: on the threshold of success. Expert Opin Emerg Drugs 13: 295-308, 2008.
    OpenUrlCrossRefPubMed
  58. ↵
    1. Chapman PB
    : Melanoma vaccines. Semin Oncol 34: 516-523, 2007.
    OpenUrlPubMed
  59. ↵
    1. Aarntzen EH,
    2. Figdor CG,
    3. Adema GJ,
    4. Punt CJ,
    5. de Vries IJ
    : Dendritic cell vaccination and immune monitoring. Cancer Immunol Immunother 57: 1559-1568, 2008.
    OpenUrlCrossRefPubMed
  60. ↵
    1. Wada J,
    2. Yamasaki A,
    3. Nagai S,
    4. Yanai K,
    5. Fuchino K,
    6. Kameda C,
    7. Tanaka H,
    8. Koga K,
    9. Nakashima H,
    10. Nakamura M,
    11. Tanaka M,
    12. Katano M,
    13. Morisaki T
    : Regulatory T-cells are possible effect prediction markers of immunotherapy for cancer patients. Anticancer Res 28: 2401-2408, 2008.
    OpenUrlAbstract/FREE Full Text
  61. ↵
    1. Burgdorf SK,
    2. Claesson MH,
    3. Nielsen HJ,
    4. Rosenberg J
    : Changes in cytokine and biomarker blood levels in patients with colorectal cancer during dendritic cell-based vaccination. Acta Oncol 48: 1157-64, 2009.
    OpenUrlPubMed
  62. ↵
    1. Schattenberg AV,
    2. Dolstra H
    : Cellular adoptive immunotherapy after allogeneic stem cell transplantation. Curr Opin Oncol 17: 617-621, 2005.
    OpenUrlPubMed
  63. ↵
    1. Huff CA,
    2. Fuchs EJ,
    3. Smith BD,
    4. Blackford A,
    5. Garrett-Mayer E,
    6. Brodsky RA,
    7. Flinn IW,
    8. Ambinder RF,
    9. Borrello IM,
    10. Matsui WH,
    11. Vogelsang GB,
    12. Griffin CA,
    13. Luznik L,
    14. Jones RJ
    : Graft-versus-host reactions and the effectiveness of donor lymphocyte infusions. Biol Blood Marrow Transplant 12: 414-421, 2006.
    OpenUrlCrossRefPubMed
  64. ↵
    1. Rosenberg SA,
    2. Dudley ME
    : Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr Opin Immunol 21: 233-240, 2009.
    OpenUrlCrossRefPubMed
  65. ↵
    1. Hodes RJ,
    2. Hathcock KS,
    3. Weng NP
    : Telomeres in T- and B-cells. Nat Rev Immunol 2: 699-706, 2002.
    OpenUrlCrossRefPubMed
  66. ↵
    1. Ochsenbein AF,
    2. Riddell SR,
    3. Brown M,
    4. Corey L,
    5. Baerlocher GM,
    6. Lansdorp PM,
    7. Greenberg PD
    : CD27 expression promotes long-term survival of functional effector-memory CD8+ cytotoxic T lymphocytes in HIV-infected patients. J Exp Med 200: 1407-1417, 2004.
    OpenUrlAbstract/FREE Full Text
  67. ↵
    1. Characiejus D,
    2. Hodzic J,
    3. Jacobs JJL
    : “First do no harm” and the importance of prediction in oncology. EPMA J 1: 369-375, 2010.
    OpenUrlCrossRefPubMed
  68. ↵
    1. Yu P,
    2. Fu YX
    : Tumor-infiltrating T lymphocytes: Friends or foes? Lab Invest 86: 231-245, 2006.
    OpenUrlCrossRefPubMed
  69. ↵
    1. Farrar JD,
    2. Katz KH,
    3. Windsor J,
    4. Thrush G,
    5. Scheuermann RH,
    6. Uhr JW,
    7. Street NE
    : Cancer dormancy. VII. A regulatory role for CD8+ T-cells and IFN-γ in establishing and maintaining the tumor-dormant state. J Immunol 162: 2842-2849, 1999.
    OpenUrlAbstract/FREE Full Text
  70. ↵
    1. Focosi D,
    2. Bestagno M,
    3. Burrone O,
    4. Petrini M
    : CD57+ T lymphocytes and functional immune deficiency. J Leukoc Biol 87: 107-116, 2010.
    OpenUrlCrossRefPubMed
  71. ↵
    1. Goronzy JJ,
    2. Fulbright JW,
    3. Crowson CS,
    4. Poland GA,
    5. O'Fallon WM,
    6. Weyand CM
    : Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals. J Virol 75: 12182-12187, 2001.
    OpenUrlAbstract/FREE Full Text
  72. ↵
    1. Gattinoni L,
    2. Klebanoff CA,
    3. Palmer DC,
    4. Wrzesinski C,
    5. Kerstann K,
    6. Yu Z,
    7. Finkelstein SE,
    8. Theoret MR,
    9. Rosenberg SA,
    10. Restifo NP
    : Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T-cells. J Clin Invest 115: 1616-1626, 2005.
    OpenUrlCrossRefPubMed
  73. ↵
    1. Karan D,
    2. Krieg AM,
    3. Lubaroff DM
    : Paradoxical enhancement of CD8 T-cell-dependent anti tumor protection despite reduced CD8 T-cell responses with addition of a TLR9 agonist to a tumor vaccine. Int J Cancer 121: 1520-1528, 2007.
    OpenUrlCrossRefPubMed
  74. ↵
    1. Muris JJ,
    2. Meijer CJ,
    3. Cillessen SA,
    4. Vos W,
    5. Kummer JA,
    6. Bladergroen BA,
    7. Bogman MJ,
    8. MacKenzie MA,
    9. Jiwa NM,
    10. Siegenbeek van Heukelom LH,
    11. Ossenkoppele GJ,
    12. Oudejans JJ
    : Prognostic significance of activated cytotoxic T-lymphocytes in primary nodal diffuse large B-cell lymphomas. Leukemia 18: 589-596, 2004.
    OpenUrlCrossRefPubMed
  75. ↵
    1. Mackall CL,
    2. Fleisher TA,
    3. Brown MR,
    4. Andrich MP,
    5. Chen CC,
    6. Feuerstein IM,
    7. Magrath IT,
    8. Wexler LH,
    9. Dimitrov DS,
    10. Gress RE
    : Distinctions between CD8+ and CD4+ T-cell regenerative pathways result in prolonged T-cell subset imbalance after intensive chemotherapy. Blood 89: 3700-3707, 1997.
    OpenUrlAbstract/FREE Full Text
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Prediction of Response in Cancer Immunotherapy
DAINIUS CHARACIEJUS, JOHN J.L. JACOBS, VITA PAŠUKONIENĖ, NIJOLĖ KAZLAUSKAITĖ, VITA DANILEVIČIŪTĖ, MYKOLAS MAURICAS, WILLEM DEN OTTER
Anticancer Research Feb 2011, 31 (2) 639-647;
Twitter logo Facebook logo Mendeley logo

Jump to section