Research ArticleExperimental Studies

Immunohistochemical Analysis of Common Cancer Antigens in Head and Neck Squamous Cell Carcinoma

YOHEI MORISHITA, KAZUMASA TAKENOUCHI, SHINGO SAKASHITA, KAZUTO MATSUURA, RYUICHI HAYASHI and TETSUYA NAKATSURA
Anticancer Research December 2022, 42 (12) 5751-5761; DOI: https://doi.org/10.21873/anticanres.16082

Abstract

Background/Aim: The prognosis of recurring and metastatic head and neck squamous cell carcinoma (HNSCC) is poor. Although immune checkpoint inhibitors have expanded the treatment options for HNSCC, the response rates are low. Alternatively, cancer vaccines and T-cell therapies are being developed. Identification of useful common cancer antigens and confirmation of human leukocyte antigen (HLA) class I expression are required. Materials and Methods: Immunohistochemistry analyses were performed for 10 antigens (FOXM1, TGFBI, SPARC, HSP105α, WT1, AFP, GPC3, PP-RP, KIF20A, KM-HN-1) and HLA class I using specimens of 56 surgical cases. Staining intensity, percentage of stain-positive areas, and localization of staining in the tumor cells and normal tissue were evaluated. Results: Staining of FOXM1, TGFBI, SPARC, and HSP105α was more predominant in tumor cells than that in normal cells. The expression rates of these antigens in tumor cells were 60.7%, 58.9%, 73.2%, and 50.0%, respectively. Regarding sites, the expression rates of these antigens in oral cancer were high at 57.1%, 71.4%, 81.0%, and 66.7%, respectively. Furthermore, the expression of HLA class I was 83.9% in all cases. Of these, 68.1% showed expression on the plasma membrane. Conclusion: FOXM1, TGFBI, SPARC, and HSP105α could be useful common cancer antigens, and HLA class I is expressed on the plasma membrane of cancer cells in many cases. The results suggest that cancer vaccines and T-cell therapy may be clinically viable options for HNSCC treatment.

Key Words:

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer globally, with more than 1 million annual cases (1). The standard treatment is surgery, radiation therapy, and chemotherapy; the 5-year survival rate is approximately 60% (2-5). HNSCC local recurrence is high, while 30% of the cases develop distant metastasis, and treatment options to manage such spread are limited (6). In recent times, immune checkpoint inhibitors have been approved for HNSCC treatment refractory to chemotherapy, but the response rate is only approximately 20% (7, 8). Hence, inhibition of immune checkpoints alone is insufficient to reactivate the compromised immunity of patients with HNSCC, and new treatments are desired. Cancer vaccines, such as peptide and mRNA vaccines, and T-cell therapies, such as T cell receptor (TCR)-T cell and CAR (chimeric antigen receptor)-T cell therapies, are attractive new treatment developments. Cancer vaccines produce anti-tumor effects by inducing cytotoxic T lymphocytes (CTLs) against tumor cells possessing the same antigen. Previously, we discovered Glypican-3 (GPC3), a common cancer antigen specifically expressed in hepatocellular carcinoma (HCC) and developed a peptide vaccine targeting GPC3 that was shown to be effective against HCC (9-14). Furthermore, CAR-T cell therapy, which produced remarkable therapeutic results in B-cell lymphoma, was approved worldwide, bringing T-cell therapy into the limelight (15). Hence, cancer vaccines and T-cell therapies can also be clinically useful for HNSCC. In this study, the expression of common cancer antigens and human leukocyte antigen (HLA) class I were examined by immunohistochemistry (IHC) to form the basis for the development of cancer vaccines and T-cell therapies for HNSCC. No previous report has comprehensively analyzed the expression of common cancer antigens and HLA class I in HNSCC across the primary sites.

Materials and Methods

Materials. This study selected 1) recent cases considering the preservation of the surgical specimen block, 2) cases where both the tumor and normal tissues were preserved in the same block to allow comparative analysis, and 3) cases involving the oral cavity, oropharynx, and hypopharynx, which are the main primary sites of HNSCC. A total of 57 surgical cases from March 2017 to July 2020 were included, consisting of 21 cases of oral cavity cancer (15 tongue cancer, four buccal mucosa cancers, one hypogingival cancer, and one floor of mouth cancer), 15 cases of oropharyngeal cancer (p16–), 15 cases of oropharyngeal cancer (p16+), and six cases of hypopharyngeal cancer. The patients provided written informed consent for the publication of this study. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethical Review Committee of our institution.

Tumor antigen & HLA class I. IHC was used to identify forkhead box protein M1 (FOXM1), Wilms’ tumor protein 1 (WT1), α fetoprotein (AFP), proliferation potential-related protein (PP-RP)/retinoblastoma-binding protein 6 (RBBP6), transforming growth factor beta-induced protein (TGFBI), secreted protein acidic and rich in cysteine (SPARC), and Glypican 3 (GPC3). In addition, heat shock protein 105α (HSP105α), kinesin family member 20A (KIF20A), KM-HN-1/Coiled-Coil Expression of 10 antigens of Domain-Containing Protein 110 (CCDC110), and HLA class I. The antibodies used are listed in Table I.

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Table I.

Antibody information.

IHC. Formalin-fixed paraffin-embedded tissues were used; paraffin sections of 4 μm thickness were prepared, deparaffinized with xylene, and rehydrated with ethanol. Endogenous peroxidase was quenched/blocked with 0.3% H2O2. Antigen activation was performed by microwave heat treatment in TRS9 buffer (pH 9.0, Dako/Agilent, Santa Clara, CA, USA) at 95°C for 20 min. Primary antibodies were incubated at room temperature for 1 h. Mouse/rabbit Envision Polymer (Dako/Agilent) was then used as the secondary antibody and incubated at room temperature for 30 min. 3-3′-Diaminobentidine color development solution was added to the slides and counterstained with hematoxylin and eosin (H&E). The slides were dehydrated with xylene and sealed with cover glasses.

Evaluation of staining. The staining intensity of tumor cells and normal tissue was scored for each of the 10 antigens examined as follows: negative: 0, weakly positive: 1, weakly to strongly positive: 2, and strongly positive: 3. Furthermore, the percentages of positive staining were scored as follows: 0-10%: 0, 10-39%: 1, 40-69%: 2, 70-100%: 3. The scores were subsequently summed and graded into the following three levels: low, middle, and high for a total score of 0-2, 3-4, and 5-6, respectively. The grading was defined as tumor (T)>normal (N), T=N, and T<N for cases in which tumor cells predominated, tumor cells and normal tissue were equal, and normal tissue predominated, respectively. For example, when the staining intensity of tumor cells in a case was 3 (strongly positive), with 80% positivity (score of 3), the grade was high. Localization of staining was also evaluated in tumor cells, epithelial and subepithelial normal tissues. In addition, in HLA class I, the presence and localization of staining were evaluated in tumor cells and normal tissues for each case. Among the 57 cases selected, one case of oropharyngeal carcinoma (p16+) was excluded from the analysis because it was not stained by all antibodies and was therefore considered an inappropriate specimen. Therefore, 56 cases were analyzed, including 21 oral cancer, 15 oropharyngeal cancer (p16–), 14 oropharyngeal cancer (p16+), and six hypopharyngeal cancer cases.

Results

Four antigens (FOXM1, TGFBI, SPARC, HSP105α) showed stronger immunostaining in tumor cells than that in normal tissue (Table II and Table III), whereas the other six antigens either did not stain tumor cells or showed staining equivalent to that in normal tissues (Table IV). In addition, the vital organs, such as the blood vessels and muscle tissues, were stained in the normal tissue.

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Table II.

Percentage of T>N in four validated antigens.

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Table III.

Localization of staining in four validated antigens.

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Table IV.

Staining results for each antigen by primary site.

Figure 1 and Figure 2 show representative H&E staining and FOXM1, TGFBI, SPARC, and HSP105α staining images; for these antigens, T>N and staining localization were 60.7% (34/56) and cell nucleus, 58.9% (33/56) and cytoplasm, 73.2% (41/56) and cytoplasm and fibroblasts, and 50.0% (28/56) and cytoplasm, respectively, in all cases. Furthermore, for FOXM1, T>N by primary site was 57.1% (12/21), 73.3% (11/15), 57.1% (8/14), 50% (3/6) for oral cavity, oropharynx (p16–), oropharynx (p16+), and hypopharynx, respectively. Similarly, T>N for primary site for TGFBI, SPARC, and HSP105 were 71.4% (15/21), 60.0% (9/15), 35.7% (5/14), and 66.7% (4/6), 81.0% (17/21), 73.3% (11/15), 78.6% (11/14), and 33.3% (2/6), and 66.7% (14/21), 66.7% (10/15), 28.6% (4/14), and 0.0% (0/6) for oral cavity, oropharynx (p16–), oropharynx (p16+), and hypopharynx, respectively. In all cases of WT1, AFP, and GPC3, T>N were 3.6% (2/56), 0% (0/56), and 7.1% (4/56), respectively, while in all cases of PP-RP, KIF20A, and KM-HN-1, T>N was 62.5% (35/56), 50.0% (28/56), and 50.0% (28/56), respectively.

Figure 1.
Figure 1.

H&E images of a typical case. (a) Hypopharyngeal head carcinoma, No53. (a-1) Whole image. (a-2) Tumor, 40×. (a-3) Normal part, 40×. (b) Oral cancer (tongue), No5. (b-1) Whole image. (b-2) Tumor, 40×. (b-3) Normal part, 40×. (c) Oral cancer (tongue), No4. (c-1) Whole image. (c-2) Tumor, 40×. (c-3) Normal part, 40×. (d) Carcinoma of the oropharynx (p16–), No 33. (d-1) Whole image. (d-2) Tumor, 40×. (d-3) Normal part, 40×.

Figure 2.
Figure 2.

Antigen-stained images of typical cases. (a) Hypopharyngeal carcinoma, No53, FOXM1. (a-1) General view. (a-2) Tumor area, 40×, staining in the cell nucleus. Staining intensity: 3, staining-positive area: 80%, total score: 6, grade: High. (a-3) Normal area, 40×, staining is seen in cell nuclei in the basal layer of epithelium. Staining intensity: 1, stain-positive area: 10%, total score: 1, grade: Low. (b) Oral cancer (tongue), No 5, TGFBI. (b-1) General view. (b-2) Tumor, 40×, staining in cytoplasm. Staining intensity: 3, staining-positive area: 60%, total score: 5, grade: High. (b-3) Normal area, 40×, little staining in the epithelium. Staining intensity: 1, stain-positive area: 5%, total score: 1, grade: Low. (c) Oral cancer (tongue), No 4, SPARC. (c-1) Overall view. (c-2-1,2) Tumor area, 40×, staining in the cytoplasm and fibroblasts. Staining intensity: 3, staining-positive area: 70%, total score: 6, grade: High. (c-3) Normal area, 40×, no staining in the epithelium. Staining intensity: 0, stain-positive area: 0%, total score: 0, grade: Low. (d) Carcinoma of oropharynx (p16–), No33, HSP105α. (d-1) General view. (d-2) Tumor area, 40×, staining in the cytoplasm. Staining intensity: 3, staining-positive area: 80%, total score: 6, grade: High. (d-3) Normal area, 40×, almost no staining in the epithelium. Staining intensity:1, stain-positive area: 20%, total score: 2, grade: Low.

Table V shows the results of the HLA class I staining by primary site. Of all the cases, 83.9% (47/56) showed tumor cell staining. The localization of staining was 57.4% (27/47) in the plasma membrane, 31.9% (15/47) in the cytoplasm, and 10.6% (5/47) in both the plasma membrane and cytoplasm. Positive expression rates by primary site were 95.2% (20/21), 86.7% (13/15), 64.2% (9/14), and 83.3% (5/6) in the oral cavity, oropharynx (p16–), oropharynx (p16+), and hypopharynx, respectively. HLA class I staining images of the representative cases are shown in Figure 3.

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Table V.

Staining results for HLA class I by primary site.

Figure 3.
Figure 3.

HLA class I image of a typical case. (a) Hypopharyngeal carcinoma, No53. (a-1) General view. (a-2) Tumor, 40×. Staining is observed on the cell membrane. (a-3) Normal area, 40×. Staining is seen on the cell membrane. (b) Oral cancer (tongue), No 5. (b-1) General view. (b-2) Tumor, 40×. Staining is observed in the cytoplasm. (b-3) Normal area, 40×. Staining is seen in the cell membrane of the basal layer of the epithelium. (c) Oral cancer (tongue), No 4. (c-1) General view. (c-2) Tumor, 40×. Staining is observed on the cell membrane. (c-3) Normal area, 40×. No staining in the epithelium. (d) Carcinoma of oropharynx (p16–), No 33. (d-1) General view. (d-2) Tumor area, 40×. Staining is seen on the cell membrane. (d-3) Normal area, 40×. Staining is observed in the cell membrane of the basal layer of the epithelium.

A list showing the prevalence of T>N of the four antigens, FOXM1, TGFBI, SPARC, and HSP105α, in each case, is shown in Table VI and summarized by the primary site in Table VII. Of the total cases, 92.9% (52/56) expressed any of these four antigens, and 84.6% (44/52) of these cases also expressed HLA class I.

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Table VI.

Focusing on the staining results of FOXM1, TGFBI, SPARC, HSP105α, and HLA class I in each case.

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Table VII.

Percentage of effective antigen counts at each primary site (in FOXM1, TGFBI, SPARC, and HSP105α).

Discussion

Cancer immunotherapy has been attracting attention with the advent of immune checkpoint inhibitors. In cancer immunotherapy, T cells must infiltrate and attack cancer cells to exert sufficient therapeutic effect; the arsenals are cancer vaccines targeting common cancer antigens and neoantigens and gene-modified T-cell therapies such as CAR-T and TCR-T. In recent years, T-cell therapies have gained prominence with the worldwide approval of CAR-T cell therapy, which has produced remarkable results in treating CD19-positive B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma (15). Thus, the development of cancer immunotherapy is steadily advancing and attracting attention as a new cancer treatment.

Previously, we developed a peptide vaccine targeting GPC3 and have reported several successful results. GPC3 is a cancer antigen specifically over-expressed in hepatocellular carcinoma (HCC) and correlates with poor prognosis, making it an ideal target for cancer vaccines against HCC. In addition, clinical trials have confirmed the safety of GPC3-derived peptide vaccines and correlated with prolonged overall survival in patients with advanced HCC (9-14). Conversely, the development of such cancer vaccines for HNSCC is still in progress. Among them, clinical trials of vaccines targeting P53, P16, CDCA1/LY6K/IMP3, and survivin-2B have been reported (16-19). In particular, a multivalent vaccine targeting CDCA1/LY6K/IMP3 has passed Phase II clinical trials. This clinical trial showed an overall survival benefit in the group of patients carrying HLA-A24who received the vaccine. Scattered reports of ongoing clinical trials and in vitro studies confirm efficacy. Overall, cancer vaccines have the potential to become a clinically viable option for HNSCC treatment (20, 21). Cancer vaccines recognize antigens that serve as cues for the immune system to differentiate between normal and cancer cells. This is followed by the action of T cells that infiltrate and attack cancer cells. In addition, it should be considered that the conditions for a useful antigen for HNSCC are not limited to the primary site. In this study, we immunohistochemically analyzed 10 antigens and HLA class I, which are recognized as specific antigens in other carcinomas but are still unknown in HNSCC, across multiple primary sites. The results showed that FOXM1, TGFBI, SPARC, and HSP105α might be useful as cancer antigens.

The Forkhead family of transcription factors includes regulators with many important functions in embryonic development and adult tissues (22). These proteins also play important roles in cancer progression. The most important transcription factor involved in many oncogenic processes is FOXM1 (23, 24). FOXM1 has been reported to be involved in HNSCC; hence, it is expected to have clinical applications (25-28). In the present analysis, FOXM1 was found to be expressed in the nuclei of tumor cells, and its expression was particularly high in the primary site of oropharyngeal carcinoma (p16–). Since the efficacy of radiotherapy and chemotherapy is known to be inferior for oropharyngeal carcinoma (p16–), FOXM1-based vaccine may be beneficial for targeting oropharyngeal carcinoma (p16–).

TGFBI is a secreted extracellular matrix protein induced by TGF-β that mediates cell adhesion to extracellular proteins such as collagen, fibronectin, and laminin via integrin binding. They play roles in morphogenesis, cell adhesion, migration, differentiation, inflammation, tumorigenesis, and metastasis (29, 30). In recent years, TGFBI has been extensively studied in various carcinomas, and it has been reported to be involved in HNSCC, such as oral and oropharyngeal carcinoma (31, 32). In the present analysis, TGFBI was found to be expressed in the cytoplasm of tumor cells, and its expression was high in cases of oral cancer at the primary site. Since oral cancer is sometimes resistant to radiotherapy and chemotherapy, TGFBI may be a useful target to improve the treatment outcome of oral cancer. It should also be noted that this antigen was the most highly expressed among the four antigens in patients with hypopharyngeal carcinoma.

SPARC, also called osteonectin, is a matrix-associated protein that causes cell shape changes, inhibits cell cycle progression, and affects extracellular matrix synthesis (33). A correlation between SPARC expression and malignant transformation and survival has also been demonstrated (34, 35). It has been reported that SPARC is involved in HNSCC involving the hypopharynx (36). In the present analysis, expression was confirmed in fibroblasts surrounding tumors and also in tumor cytoplasm in oral cancer. This is a very valuable finding, as there are no reports of expression in fibroblasts and tumor. In addition, since the gene is highly expressed at all primary sites except hypopharyngeal carcinoma, it has the potential to be an important target in terms of broad coverage.

HSPs are involved in protein homeostasis under stressful conditions. HSPs function as molecular chaperones and bind to client proteins to form complexes with multiple molecules. It has been suggested that disruption of these functions leads to cancer development (37-39). HSP105α is a high molecular weight protein belonging to HSP105/110, a subgroup of the HSP70 family. HSP105α has only recently been studied, and its expression has been reported in many carcinomas, including HNSCC (40-43). In the present analysis, expression was shown in the tumor cytoplasm, and at the primary site, the expression was high in oropharyngeal (p16–) and oral cavity carcinomas.

Of the four antigens, SPARC was the most specifically expressed antigen on tumor cells and may be the best target for peptide vaccines; however, the low expression in hypopharyngeal carcinoma is an obstacle. In this study’s analysis, 92.3% of the cases strongly expressed one of the four antigens tested, suggesting that a multivalent vaccine combining these four antigens would be an effective vaccine for HNSCC, which is characterized by having a diverse group of primary sites.

When HLA class I is expressed on the surface of cancer cells, cytotoxic T lymphocytes can recognize and eliminate them. Hence, understanding HLA class I expression is critical for the development of cancer vaccine and T-cell therapies. In the present analysis, HLA class I was expressed on the plasma membrane of cancer cells in more than half of the cases, regardless of the primary site, suggesting that HLA class I may be clinically beneficial for developing cancer vaccines and T-cell therapies against HNSCC. Additionally, we also observed cases in which HLA class I was not expressed in any of the primary sites, particularly in oropharyngeal carcinoma (p16+). This indicates the existence of a possible mechanism of escaping from anti-tumor immunity in some cases of HNSCC.

Conclusion

FOXM1, TGFBI, SPARC, and HSP105α are identified as useful common cancer antigens with high expression in tumor areas. In addition, expression of HLA class I was observed in the plasma membrane of cancer cells in many cases. Cancer vaccines and T-cell therapies targeting these antigens may be advantageous for HNSCC treatment.

Acknowledgements

The Authors would like to thank Editage (www.editage.com) for English language editing.

Footnotes

  • Authors’ Contributions

    Y.M, K.T and T.N participated in the study design. Y.M, K.M, R.H and T.N supplied materials. Y.M, K.T and S.S performed immunohistochemical analysis. Y.M, K.T and T.N wrote the manuscript. All Authors contributed to discussion and review of the final manuscript.

  • Conflicts of Interest

    All Authors declare no conflicts of interest in relation to this study.

  • Funding

    This work was supported in part by the National Cancer Center Research and Development Fund (2022-A-9).

  • Received July 30, 2022.
  • Revision received September 27, 2022.
  • Accepted October 5, 2022.

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Immunohistochemical Analysis of Common Cancer Antigens in Head and Neck Squamous Cell Carcinoma
YOHEI MORISHITA, KAZUMASA TAKENOUCHI, SHINGO SAKASHITA, KAZUTO MATSUURA, RYUICHI HAYASHI, TETSUYA NAKATSURA
Anticancer Research Dec 2022, 42 (12) 5751-5761; DOI: 10.21873/anticanres.16082
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