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Updated: Oct 21, 2025
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
Tumor-infiltrating CD8+ T cells recognize a heterogeneously expressed functional neoantigen in clear cell renal cell
Masahiro Matsuki1,2, Yoshihiko Hirohashi3, Munehide Nakatsugawa1,4
1Department of Pathology, Sapporo Medical University School of Medicine, South-1 West-17, Chuo-Ku, Sapporo, 060-8556, Japan.
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.
Insights
Tumor heterogeneity in clear cell renal cell carcinoma (ccRCC) impacts immunotherapy response. Researchers identified a novel neoantigen in high-grade ccRCC, explaining why some tumor cells evade immune attack.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Immune checkpoint inhibitors (ICIs) show limited response rates in cancer immunotherapy.
- Tumor cell heterogeneity is a key factor in immunotherapy resistance.
- The specificity of tumor-infiltrating lymphocytes (TILs) in renal cell carcinoma (RCC) remains unclear.
Purpose of the Study:
- To investigate the role of tumor heterogeneity in clear cell RCC (ccRCC) and its impact on TIL recognition.
- To identify specific neoantigens driving anti-tumor immune responses in ccRCC.
Main Methods:
- Analysis of a ccRCC tumor exhibiting macroscopic and microscopic heterogeneity.
- Isolation of a tumor cell line (1226 RCC cells) and TILs from high-grade ccRCC.
- Identification of a neoantigen peptide (YVVPGSPCL) recognized by a TIL clone, encoded by a TNS1 gene mutation.
Main Results:
- A novel neoantigen peptide (YVVPGSPCL) was identified, derived from a TNS1 gene missense mutation (S1309Y) in high-grade ccRCC.
- The TNS1 mutation was absent in low-grade ccRCC lesions.
- The identified TIL clone specifically recognized high-grade ccRCC cells but not low-grade ccRCC cells.
- The TNS1 mutation was linked to increased cell migration through gene over-expression.
Conclusions:
- Macroscopic and microscopic tumor heterogeneity in ccRCC is associated with diverse gene mutations and differential TIL reactivity.
- Understanding tumor-specific neoantigens is crucial for improving ccRCC immunotherapy efficacy.
- Targeting heterogeneous mutations may enhance treatment outcomes for ccRCC patients.
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