Tumor-infiltrating CD8+ T cells recognize a heterogeneously expressed functional neoantigen in clear cell renal cell carcinoma.
Masahiro MatsukiYoshihiko HirohashiMunehide NakatsugawaAiko MuraiTerufumi KuboShinichi HashimotoSerina TokitaKenji MurataTakayuki KanasekiTomohide TsukaharaSachiyo NishidaToshiaki TanakaHiroshi KitamuraNaoya MasumoriToshihiko TorigoePublished in: Cancer immunology, immunotherapy : CII (2021)
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.
Keyphrases
- low grade
- high grade
- renal cell carcinoma
- induced apoptosis
- cell migration
- single cell
- peripheral blood
- endothelial cells
- cell cycle arrest
- poor prognosis
- stem cells
- genome wide
- endoplasmic reticulum stress
- oxidative stress
- signaling pathway
- cell death
- autism spectrum disorder
- cell proliferation
- clear cell
- transcription factor
- cell therapy
- dna methylation