Immune checkpoint inhibitors (ICIs) are used in cancer immunotherapy to block programmed death-1 and cytotoxic T-lymphocyte antigen 4, but the response rate for ICIs is still low and tumor cell heterogeneity is considered to be responsible for resistance to immunotherapy. Tumor-infiltrating lymphocytes (TILs) have an essential role in the anti-tumor effect of cancer immunotherapy; however, the specificity of TILs in renal cell carcinoma (RCC) is elusive. In this study, we analyzed a 58-year-old case with clear cell RCC (ccRCC) with the tumor showing macroscopic and microscopic heterogeneity. The tumor was composed of low-grade and high-grade ccRCC. A tumor cell line (1226 RCC cells) and TILs were isolated from the high-grade ccRCC lesion, and a TIL clone recognized a novel neoantigen peptide (YVVPGSPCL) encoded by a missense mutation of the tensin 1 (TNS1) gene in a human leukocyte antigen-C*03:03-restricted fashion. The TNS1 gene mutation was not detected in the low-grade ccRCC lesion and the TIL clone did not recognized low-grade ccRCC cells. The missense mutation of TNS1 encoding the S1309Y mutation was found to be related to cell migration by gene over-expression. These findings suggest that macroscopically and microscopically heterogenous tumors might show heterogenous gene mutations and reactivity to TILs.
Cancer immunology, immunotherapy : CII. 2021 Sep 07 [Epub ahead of print]
Masahiro Matsuki, Yoshihiko Hirohashi, Munehide Nakatsugawa, Aiko Murai, Terufumi Kubo, Shinichi Hashimoto, Serina Tokita, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Sachiyo Nishida, Toshiaki Tanaka, Hiroshi Kitamura, Naoya Masumori, Toshihiko Torigoe
Department of Pathology, Sapporo Medical University School of Medicine, South-1 West-17, Chuo-Ku, Sapporo, 060-8556, Japan., Department of Pathology, Sapporo Medical University School of Medicine, South-1 West-17, Chuo-Ku, Sapporo, 060-8556, Japan. ., Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, 641-8509, Japan., Department of Urology, Sapporo Medical University School of Medicine, Sapporo, 060-8556, Japan., Department of Urology, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan., Department of Pathology, Sapporo Medical University School of Medicine, South-1 West-17, Chuo-Ku, Sapporo, 060-8556, Japan. .