Abstract
Renal cell carcinoma (RCC) is known to respond to immune checkpoint blockade (ICB) therapy, whereas there has been limited analysis of T-cell responses to RCC. In this study, we utilized human carbonic anhydrase 9 (hCA9) as a model neoantigen of mouse RENCA RCC. hCA9-expressing RENCA RCC (RENCA/hCA9) cells were rejected in young mice but grew in aged mice. CD8+ T cells were the primary effector cells involved in rejection in young mice, whereas CD4+ T cells participated at the early stage. Screening of a panel of hCA9-derived peptides revealed that mouse CD8+ T cells responded to hCA9288–296 peptide. Mouse CD4+ T cells responded to lysates of RENCA/hCA9, but not RENCA cells, and showed reactivity to hCA9 276–290, which shares three amino acids with hCA9 288–296 peptide. Immunohistochemistry analysis revealed that few T cells infiltrated RENCA/hCA9 tissues in aged mice. ICB therapy of anti-PD-1/anti-CTLA-4 antibodies promoted T-cell infiltration into tumor tissues, whereas no definite antitumor effect was observed. However, additional combination with cyclophosphamide or axitinib, a vascular endothelial growth factor receptor inhibitor, induced complete regression in half of the RENCA/hCA9-bearing aged mice with increased expression of PD-L1 in tumor tissues. These results indicate that hCA9 can be a useful model neoantigen to investigate antitumor T-cell responses in mice with RCC, and that RENCA/hCA9 in aged mice can serve as a non-inflamed ‘cold’ tumor model facilitating the development of effective combined immunotherapies for RCC.
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Acknowledgements
This study was supported in part by JSPS KAKENHI Grants (No. 17K07217 to M Harada, No. 17K11301 to K Yoshikawa, and No. 19H03794 for H Uemura), Suzuken Memorial Foundation to Y Iida, and SHIMANE “SUIGAN” Project to M Harada.
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Harada, M., Iida, Y., Kotani, H. et al. T-cell responses and combined immunotherapy against human carbonic anhydrase 9-expressing mouse renal cell carcinoma. Cancer Immunol Immunother 71, 339–352 (2022). https://doi.org/10.1007/s00262-021-02992-7
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DOI: https://doi.org/10.1007/s00262-021-02992-7