T-cell exhaustion signatures vary with tumor type and are severe in glioblastoma

Karolina Woroniecka, Pakawat Chongsathidkiet, Kristen Rhodin, Hanna Kemeny, Cosette Dechant, S. Harrison Farber, Aladine A. Elsamadicy, Xiuyu Cui, Shohei Koyama, Christina Jackson, Landon J. Hansen, Tanner M. Johanns, Luis Sanchez-Perez, Vidyalakshmi Chandramohan, Yen Rei Andrea Yu, Darell D. Bigner, Amber Giles, Patrick Healy, Glenn Dranoff, Kent J. WeinholdGavin P. Dunn, Peter E. Fecci

Research output: Contribution to journalArticlepeer-review

246 Scopus citations

Abstract

Purpose: T-cell dysfunction is a hallmark of glioblastoma (GBM). Although anergy and tolerance have been well characterized, T-cell exhaustion remains relatively unexplored. Exhaustion, characterized in part by the upregulation of multiple immune checkpoints, is a known contributor to failures amid immune checkpoint blockade, a strategy that has lacked success thus far in GBM. This study is among the first to examine, and credential as bona fide, exhaustion among T cells infiltrating human and murine GBM. Experimental Design: Tumor-infiltrating and peripheral blood lymphocytes (TILs and PBLs) were isolated from patients with GBM. Levels of exhaustion-associated inhibitory receptors and poststimulation levels of the cytokines IFNg, TNFa, and IL2 were assessed by flow cytometry. T-cell receptor Vb chain expansion was also assessed in TILs and PBLs. Similar analysis was extended to TILs isolated from intracranial and subcutaneous immunocom-petent murine models of glioma, breast, lung, and melanoma cancers. Results: Our data reveal that GBM elicits a particularly severe T-cell exhaustion signature among infiltrating T cells characterized by: (1) prominent upregulation of multiple immune checkpoints; (2) stereotyped T-cell transcriptional programs matching classical virus-induced exhaustion; and (3) notable T-cell hyporesponsiveness in tumor-specific T cells. Exhaustion signatures differ predictably with tumor identity, but remain stable across manipulated tumor locations. Conclusions: Distinct cancers possess similarly distinct mechanisms for exhausting T cells. The poor TIL function and severe exhaustion observed in GBM highlight the need to better understand this tumor-imposed mode of T-cell dysfunction in order to formulate effective immunotherapeutic strategies targeting GBM.

Original languageEnglish
Pages (from-to)4175-4186
Number of pages12
JournalClinical Cancer Research
Volume24
Issue number17
DOIs
StatePublished - Sep 1 2018

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