T-cell responses and combined immunotherapy against human carbonic anhydrase 9-expressing mouse renal cell carcinoma
T-cell responses and combined immunotherapy against human carbonic anhydrase 9-expressing mouse renal cell carcinoma
复制标题
DOI：
10.1007/s00262-021-02992-7
复制
发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
M. Harada;Y. Iida;H. Kotani;T. Minami;Y. Komohara;M. Eto;K. Yoshikawa;H. Uemura
中科院分区：
文献类型：
--
作者：
M. Harada;Y. Iida;H. Kotani;T. Minami;Y. Komohara;M. Eto;K. Yoshikawa;H. Uemura
已知肾细胞癌（RCC）对免疫检查点阻断（ICB）治疗有反应，而对RCC的T细胞反应的分析有限。在本研究中，我们利用人碳酸酐酶9（hCA 9）作为小鼠RENCA RCC的模型新抗原。表达hCA 9的RENCA RCC（RENCA/hCA 9）细胞在年轻小鼠中被排斥，但在老年小鼠中生长。在幼龄小鼠中，CD 8 +T细胞是参与排斥反应的主要效应细胞，而CD 4 +T细胞在早期参与。一组hCA 9衍生肽的筛选显示小鼠CD 8 +T细胞对hCA 9288 - 296肽有应答。小鼠CD 4 +T细胞对RENCA/hCA 9的裂解物有反应，但对RENCA细胞无反应，并显示出对hCA 9276 -290的反应性，hCA 9276 -290与hCA 9288 - 296肽共有三个氨基酸。免疫组织化学分析显示，在老年小鼠的RENCA/hCA 9组织中很少有T细胞浸润。抗PD-1/抗CTLA-4抗体的ICB治疗促进了T细胞向肿瘤组织的浸润，但没有观察到明确的抗肿瘤作用。然而，与环磷酰胺或阿西替尼（一种血管内皮生长因子受体抑制剂）的额外组合诱导一半携带RENCA/hCA 9的老龄小鼠完全消退，肿瘤组织中PD-L1表达增加。这些结果表明，hCA 9可以是一个有用的模型新抗原，以研究抗肿瘤T细胞反应的小鼠与RCC，和RENCA/hCA 9在老年小鼠可以作为一个非炎症的“冷”肿瘤模型，促进发展有效的联合免疫治疗RCC。
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 hCA9288–296peptide. Mouse CD4+T cells responded to lysates of RENCA/hCA9, but not RENCA cells, and showed reactivity to hCA9276–290, which shares three amino acids with hCA9288–296peptide. 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.