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Tumor-infiltrating CD8+ T cells recognize a heterogeneously expressed functional neoantigen in clear cell renal cell carcinoma

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Abstract

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.

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Acknowledgements

This work was supported by the Japan Society for the Promotion of Science (JSPS), KAKENHI for T. Torigoe (17H01540) and Y. Hirohashi (20H03460). This work was also supported by the Japan Agency for Medical Research and Development (AMED), the Project for Cancer Research and Therapeutic Evolution (P-CREATE) for T. Torigoe (16770510) and T. Kanaseki (20cm0106352h0002), and the Japan Science and Technology Agency (JST), CREST Grant Number JPMJCR15G3 for S. Hashimoto.

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  1. Department of Pathology, Sapporo Medical University School of Medicine, South-1 West-17, Chuo-Ku, Sapporo, 060-8556, Japan

    Masahiro Matsuki, Yoshihiko Hirohashi, Munehide Nakatsugawa, Aiko Murai, Terufumi Kubo, Serina Tokita, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara & Toshihiko Torigoe

  2. Department of Urology, Sapporo Medical University School of Medicine, Sapporo, 060-8556, Japan

    Masahiro Matsuki, Sachiyo Nishida, Toshiaki Tanaka & Naoya Masumori

  3. Department of Diagnostic Pathology, Tokyo Medical University Hachioji Medical Center, Hachioji, Tokyo, 193-0998, Japan

    Munehide Nakatsugawa

  4. Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, 641-8509, Japan

    Shinichi Hashimoto

  5. Department of Urology, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Hiroshi Kitamura

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  1. Masahiro Matsuki
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Masahiro Matsuki, Yoshihiko Hirohashi, Munehide Nakatsugara, Aiko Murai, Terufumi Kubo, Shinichi Hashimoto, Serina Tokita, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Sachiyo Nishida, Toshiaki Tanaka, Hiroshi Kitamura, Naoya Masumori and Toshihiko Torigoe. The first draft of the manuscript was written by Masahiro Matsuki, Yoshihiko Hirohashi, Naoya Masumori and Toshihiko Torigoe, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yoshihiko Hirohashi or Toshihiko Torigoe.

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Matsuki, M., Hirohashi, Y., Nakatsugawa, M. et al. Tumor-infiltrating CD8+ T cells recognize a heterogeneously expressed functional neoantigen in clear cell renal cell carcinoma. Cancer Immunol Immunother 71, 905–918 (2022). https://doi.org/10.1007/s00262-021-03048-6

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