Distinct exhaustion features of T lymphocytes shape the tumor-immune microenvironment with therapeutic implication in patients with non-small-cell lung cancer

Reinvigoration of T-cell exhaustion with antibodies has shown promising efficacy in patients with non-small-cell lung cancer (NSCLC). However, the characteristics of T-cell exhaustion with regard to tumor-infiltrating lymphocytes (TILs) are poorly elucidated in NSCLC. Here, we investigated the exhaustion status of TILs in NSCLC patients at the intraindividual and interindividual levels. We obtained paired peripheral blood, normal adjacent tissues, peritumoral tissues, and tumor tissues from 96 NSCLC patients. Features of T-cell exhaustion were analyzed by flow cytometry. T cells were categorized according to their programmed cell death-1 (PD-1) expression (PD-1^high, PD-1^int, and PD-1^negcells). Patients were classified based on the presence or absence of discrete PD-1^highCD8⁺TILs. Production of effector cytokines by CD8⁺TILs was measured after T-cell stimulation with or without antibodies against immune checkpoint receptors. Progressive T-cell exhaustion with marked expression of exhaustion-related markers and diminished production of effector cytokines was observed in PD-1^highCD8⁺TILs compared with PD-1^intand PD-1^negCD8⁺TILs. Patients with distinct PD-1^highCD8⁺TILs (PD-1^highexpressers) exhibited characteristics associated with a favorable anti-PD-1 response compared with those without these lymphocytes (non-PD-1^highexpressers). Combined inhibition of dual immune checkpoint receptors further restored effector cytokine production by CD8⁺TILs following T-cell stimulation. PD-1^highCD8⁺T lymphocyte populations in the peripheral blood and tumors were significantly correlated. T-cell exhaustion was differentially regulated among individual patients and was prominent in a subgroup of NSCLC patients who may benefit from PD-1 blockade or combined blockade of other immune checkpoint receptors.