TY - JOUR
T1 - T-cell responses and combined immunotherapy against human carbonic anhydrase 9-expressing mouse renal cell carcinoma
AU - Harada, Mamoru
AU - Iida, Yuichi
AU - Kotani, Hitoshi
AU - Minami, Takafumi
AU - Komohara, Yoshihiro
AU - Eto, Masatoshi
AU - Yoshikawa, Kazuhiro
AU - Uemura, Hirotsugu
N1 - Funding Information:
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.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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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U2 - 10.1007/s00262-021-02992-7
DO - 10.1007/s00262-021-02992-7
M3 - Article
C2 - 34160685
AN - SCOPUS:85108433774
VL - 71
SP - 339
EP - 352
JO - Cancer Immunology and Immunotherapy
JF - Cancer Immunology and Immunotherapy
SN - 0340-7004
IS - 2
ER -