A burned-out CD8+ T-cell subset expands in the tumor microenvironment and curbs cancer immunotherapy.

Sanmamed, Miguel F;Nie, Xinxin;Desai, Shruti S;Villaroel-Espindola, Franz;Badri, Ti;Zhao, Dejian;Kim, Anthony W;Ji, Lan;Zhang, Tianxiang;Quinlan, Edward;Cheng, Xiaoxiao;Han, Xue;Vesely, Matthew D;Nassar, Ala F;Sun, Jingwei;Zhang, Yu;Kim, Tae Kon;Wang, Jun


Specific mechanisms by which tumor infiltrating lymphocytes (TIL) become dysfunctional remain poorly understood. Here, we employed a two-pronged approach using single-cell mass cytometry and tissue imaging technologies to dissect TILs from 25 resectable and 35 advanced non-small cell lung cancer (NSCLC) patients. We identified a burned-out CD8+ TIL subset (Ebo) that specifically accumulated within the tumor microenvironment (TME), but not in adjacent non-tumoral tissues. Ebo showed the highest expression of proliferation and activation markers, but produced the lowest amount of IFNy and were the most apoptotic CD8+ TIL subset. Using a humanized patient-derived tumor xenograft model, we demonstrated that Ebo expansion occurred within the TME in a PD-1/B7-H1 pathway-dependent manner. Ebo abundance in baseline tumor tissues was associated with resistance to anti-PD therapy in NSCLC patients. Our study identifies a dysfunctional TIL subset, with distinct features from previously described exhausted T cells, and implies strategies to overcome immunotherapy resistance.

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Título de la Revista: CANCER DISCOVERY
Fecha de publicación: 2021
URL: https://cancerdiscovery.aacrjournals.org/content/early/2021/03/02/2159-8290.CD-20-0962