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

Abstract

Background: 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.

Methods: 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^neg cells). Patients were classified based on the presence or absence of discrete PD-1^high CD8⁺ TILs. Production of effector cytokines by CD8⁺ TILs was measured after T-cell stimulation with or without antibodies against immune checkpoint receptors.

Results: Progressive T-cell exhaustion with marked expression of exhaustion-related markers and diminished production of effector cytokines was observed in PD-1^high CD8⁺ TILs compared with PD-1^int and PD-1^neg CD8⁺ TILs. Patients with distinct PD-1^high CD8⁺ TILs (PD-1^high expressers) exhibited characteristics associated with a favorable anti-PD-1 response compared with those without these lymphocytes (non-PD-1^high expressers). Combined inhibition of dual immune checkpoint receptors further restored effector cytokine production by CD8⁺ TILs following T-cell stimulation. PD-1^high CD8⁺ T lymphocyte populations in the peripheral blood and tumors were significantly correlated.

Conclusions: 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.

Keywords: lung neoplasms; lymphocytes; programmed cell death 1 receptor; tumor microenvironment; tumor-infiltrating.