Balança et al. show that chronic antigen (Ag) stimulation of CD8+ T cells at a tumor site caused sequential acquisition of immune checkpoint (IC) molecules (PD-1, TIGIT, CTLA-4, and TIM3) leading to quadruple-positive (QP) cells. IC acquisition was accompanied by a loss of costimulatory receptor CD28 and TCF7 and an increase in tissue-resident memory (CD103, CD69, and CD49a), CD39, and cytotoxicity markers. In vitro, Ag stimulation and PD-1 blockade led to proliferation in PBMC, and to the reversal of exhaustion (no proliferation) in PD-1hiCD28lo TILs. QP TILs correlated with improved overall survival in response to PD-1/PDL-1 blockade in HNSCC.
Contributed by Shishir Pant
ABSTRACT: Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in cancer patients could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggest a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8+ T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor-specific CD8+ T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors leading, in situ, to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison to their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor-specific CD8+ T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated head and neck cancer patients. Our results showed that PD-1 blockade-mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors.
Author Info: (1) Cancer Research Centre of Toulouse, INSERM. (2) Cancer Research Centre of Toulouse, INSERM. (3) Cancer Research Centre of Toulouse, INSERM. (4) INSERM 1037, Institut de Recherc
Author Info: (1) Cancer Research Centre of Toulouse, INSERM. (2) Cancer Research Centre of Toulouse, INSERM. (3) Cancer Research Centre of Toulouse, INSERM. (4) INSERM 1037, Institut de Recherche en Sante Digestive. (5) Cancer Research Centre of Toulouse, INSERM. (6) Department of Medical Oncology, Institut Claudius Regaud. (7) Cancer Research Centre of Toulouse, INSERM. (8) Clinical Research Unit, IUCT-Oncopole. (9) U1037, INSERM. (10) Institut Universitaire du Cancer de Toulouse. (11) Cancer Research Centre of Toulouse, INSERM. (12) Institut Universitaire du Cancer de Toulouse. (13) Institut Universitaire du Cancer de Toulouse, INSERM UMR1037. (14) Cancer Research Center of Toulouse, INSERM UMR1037. (15) 1037, INSERM. (16) IUCT Oncopole - Institut Claudius Regaud. (17) Service d'Oncologie Medicale, Institut Claudius Regaud, IUCT-Oncopole. (18) Departement of surgical oncology, Institut Universitaire du Cancer de Toulouse. (19) Institut Universitaire du Cancer de Toulouse. (20) Institut Universitaire du Cancer de Toulouse. (21) Institut Universitaire du Cancer de Toulouse. (22) Institut Universitaire du Cancer de Toulouse. (23) Departement d'anatomie et cytologie pathologiques, Institut Universitaire du Cancer de Toulouse. (24) Institut Universitaire du Cancer de Toulouse. (25) pathology, Institut Universitaire du Cancer de Toulouse. (26) U563, INSERM. (27) Institut Universitaire du Cancer de Toulouse. (28) Clinical Research Unit, Institut Claudius Regaud, IUCT-Oncopole. (29) Pathology, Institut Claudius Regaud. (30) Cancer Research Centre of Toulouse, INSERM. (31) Cancer Research Centre of Toulouse, INSERM maha.ayyoub@inserm.fr.
