T-cell responses and combined immunotherapy against human carbonic anhydrase 9-expressing mouse renal cell carcinoma View Full Text


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Article Info

DATE

2021-06-23

AUTHORS

Mamoru Harada, Yuichi Iida, Hitoshi Kotani, Takafumi Minami, Yoshihiro Komohara, Masatoshi Eto, Kazuhiro Yoshikawa, Hirotsugu Uemura

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. More... »

PAGES

1-14

References to SciGraph publications

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/34160685


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