The prognostic relevance of tumour-infiltrating plasma cells and immunoglobulin kappa C indicates an important role of the humoral immune response in non-small cell lung cancer
Highlights
► IGKC gene and protein expression in human non-small cell lung cancer is associated with prognosis. ► IGKC is expressed in stroma-infiltrating plasma cells. ► The humoral immune response plays an important role in non-small cell lung cancer.
Introduction
Accumulating evidence supports the multifaceted role of the immune system in cancer, contrasting tumour-inhibiting properties with factors that actively promote tumour development [1]. In non-small cell lung cancer (NSCLC), the presence of various types of immune cells, as well as their tissue localisation, has been implicated in the ambiguous effects during the natural course of the disease [2], [3]. FoxP3+ regulatory T cells [4] and stromal macrophages with an M2 phenotype [5], [6] have been demonstrated to stimulate cancer growth. On the other hand, tumour-infiltrating M1 macrophages [7], stromal CD4+ T cells in the vicinity of CD8+ cytotoxic T cells [8] and the presence of dendritic cells (DCs) within tertiary lymphoid structures [9] are believed to inhibit cancer progression. Conflicting data exists with regard to tumour-infiltrating CD8+ T cells that have been associated with good as well as with poor prognosis in NSCLC [2], [10], [11]. This suggests that further clarification is needed to identify key factors that define the immune status of the in situ tissue environment in human solid tumours and its effect on tumour development.
Recently, immune modulatory strategies targeting immune checkpoints with the prototypic agent ipilimumab, an anti-cytotoxic T-lymphocyte antigen (CTLA)-4 antibody has shown survival benefit in melanoma and non-small cell lung cancer randomised clinical trials [12], [13], thus indicating that cell-mediated immunity can be successfully targeted in anti-cancer therapy. In addition to features related to cell-mediated immunity, the critical role of the humoral immune system in controlling cancer progression and predicting patient survival has recently become evident and gene expression patterns that reflect the involvement of a humoral immune response have been shown to display prognostic influence in node-negative breast cancer [14], [15].
Recently, we described the prognostic impact of IGKC gene expression in a meta-analysis comprising various cancer types, including breast cancer, colorectal cancer and NSCLC [16]. However, in that study only gene expression in fresh frozen NSCLC tissue was analysed. Since fresh frozen tissue is regularly not available in clinical routine, in the present study we analysed if the association between IGKC and patient prognosis can be confirmed on the protein level, using archived clinical lung cancer tissue and providing an opportunity to identify the IGKC expressing cell types in situ.
Section snippets
Patient cohorts
The source population consisted of surgically treated primary NSCLC patients, reported to the population-based Uppsala–Örebro Regional Lung Cancer Register consecutively from 1995 through 2005, with available fresh frozen tissue in the Uppsala Biobank at the Department of Pathology. Clinical data (histology, stage, performance status according to WHO, and smoking history) and survival times were obtained from the records of the Regional Lung Cancer Register of the Uppsala–Örebro Region in
IGKC gene expression and survival
The previously described meta-analysis [16] of the IGKC probe set (214669_x_at) was in the present study extended to include 1260 NSCLC patients from seven publicly available data sets, including the Uppsala cohort. The result confirmed the prognostic impact of IGKC gene expression with regard to overall survival (HR 0.92, CI 0.86–0.99; p = 0.021; Suppl. Fig. 1). When the clinically annotated Uppsala cohort was analysed separately (214669_x_at), IGKC expression dichotomised by the median was
Discussion
It has previously been reported that IGKC gene expression provides prognostic information in several solid tumour types. In this study we transferred this observation, based on mRNA transcript levels, to protein levels and we demonstrate that not only RNA from fresh frozen samples, but also immunohistochemically determined IGKC protein expression in FFPE tissue is associated with prognosis in NSCLC and that tumour-infiltrating plasma cells represent the source of IGKC expression. This
Acknowledgements
This work was supported by research Grants from the Lions Cancerforskningsfond (P.M. and J.B.), the Swedish Cancer Society (P.M. and J.B.), and the German Federal Ministry of Education and Research (BMBF) funded NGFN project Oncoprofile (J.G.H). The work of M.L., B.H. and J.R. was supported by the German Research Foundation (DFG, grant RA 870/5-1 and RA 870/4-1).
References (37)
- et al.
Immunity, inflammation, and cancer
Cell
(2010) - et al.
Cancer related inflammation: the macrophage connection
Cancer Lett.
(2008) - et al.
MAGE-A antigens as targets in tumour therapy
Cancer Lett.
(2012) - et al.
Anti-survivin antibody responses in lung cancer
Cancer Lett.
(2009) - et al.
Humoral immune responses of lung cancer patients against tumor antigen NY-ESO-1
Cancer Lett.
(2006) - et al.
Vaccines in non-small cell lung cancer: Rationale, combination strategies and update on clinical trials
Crit. Rev. Oncol. Hematol.
(2012) - et al.
Prognostic immune markers in non-small cell lung cancer
Clin. Cancer Res.
(2011) - et al.
Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients
Cancer
(2006) - et al.
Macrophage expression of interleukin-10 is a prognostic factor in non-small cell lung cancer
Eur. Respir. J.
(2007) - et al.
TREM-1 expression in tumor-associated macrophages and clinical outcome in lung cancer
Am. J. Respir. Crit. Care Med.
(2008)