A Burned-Out CD8+ T-cell Subset Expands in the Tumor Microenvironment and Curbs Cancer Immunotherapy
Abstract
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 patients with resectable and 35 patients with advanced non–small cell lung cancer (NSCLC). We identified a burned-out CD8+ TIL subset (Ebo) that specifically accumulated within the tumor microenvironment (TME) but not in adjacent nontumoral tissues. Ebo showed the highest expression of proliferation and activation markers but produced the lowest amount of IFNγ 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 patients with NSCLC. Our study identifies a dysfunctional TIL subset, with distinct features from previously described exhausted T cells, and implies strategies to overcome immunotherapy resistance.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 03, 2021
- Source ID
- 10.1158/2159-8290.cd-20-0962
Entities
People
- Ala F. Nassar
- Anthony W. Kim
- Dejian Zhao
- Edward J Quinlan
- Franz Villarroel‐Espíndola
- Ignacio Melero
- Jingwei Sun
- Jun Wang
- Kurt A. Schalper
- Lan Ji
- Lieping Chen
- Matthew D Vesely
- Miguel F Sanmamed
- Roy S. Herbst
- Shruti Desai
- Tae Kon Kim
- Ti Badri
- Tianxiang Zhang
- Xiaoxiao Cheng
- Xinxin Nie
- Xue Han
- Yu Zhang
Organizations
- National Center for Advancing Translational Sciences
- National Institute for Health and Care Research
- The Mark Foundation for Cancer Research
- United States Department of Defense
- University of Navarre
- Yale University