| Autor: |
Hiroyuki Kishi, Hirokazu Matsushita, Hiroshi Hamana, Yuki Tanaka, Yusuke Takahashi, Rui Yamaguchi, Hisashi Iwata, Fumiaki Watanabe, Trevor Clancy, Daisuke Muraoka, Shuichi Shinohara, Hiroyasu Komuro, Takuya Matsui, Yusuke Sugita, Ayako Demachi-Okamura, Katsuhiro Masago, Reina Nishida, Yoshiki Shigematsu, Katsutoshi Adachi, Hiroaki Kuroda, Yasunori Fukushima, Chieko Takashima, Takashi Ohki, Takashi Fukuyama, Daiki Miura, Kousuke Onoue, Kazuhide Onoguchi, Yoshiko Yamashita, Richard Stratford, Kiyoshi Doi |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Journal for ImmunoTherapy of Cancer, Vol 11, Iss 8 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2051-1426 |
| DOI: |
10.1136/jitc-2023-007180 |
| Popis: |
Background CD8+tumor infiltrating lymphocytes (TILs) are often observed in non-small cell lung cancers (NSCLC). However, the characteristics of CD8+ TILs, especially T-cell populations specific for tumor antigens, remain poorly understood.Methods High throughput single-cell RNA sequencing and single-cell T-cell receptor (TCR) sequencing were performed on CD8+ TILs from three surgically-resected lung cancer specimens. Dimensional reduction for clustering was performed using Uniform Manifold Approximation and Projection. CD8+ TIL TCR specific for the cancer/testis antigen KK-LC-1 and for predicted neoantigens were investigated. Differentially-expressed gene analysis, Gene Set Enrichment Analysis (GSEA) and single sample GSEA was performed to characterize antigen-specific T cells.Results A total of 6998 CD8+ T cells was analyzed, divided into 10 clusters according to their gene expression profile. An exhausted T-cell (exhausted T (Tex)) cluster characterized by the expression of ENTPD1 (CD39), TOX, PDCD1 (PD1), HAVCR2 (TIM3) and other genes, and by T-cell oligoclonality, was identified. The Tex TCR repertoire (Tex-TCRs) contained nine different TCR clonotypes recognizing five tumor antigens including a KK-LC-1 antigen and four neoantigens. By re-clustering the tumor antigen-specific T cells (n=140), it could be seen that the individual T-cell clonotypes were present on cells at different stages of differentiation and functional states even within the same Tex cluster. Stimulating these T cells with predicted cognate peptide indicated that TCR signal strength and subsequent T-cell proliferation and cytokine production was variable but always higher for neoantigens than KK-LC-1.Conclusions Our approach focusing on T cells with an exhausted phenotype among CD8+ TILs may facilitate the identification of tumor antigens and clarify the nature of the antigen-specific T cells to specify the promising immunotherapeutic targets in patients with NSCLC. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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