Distinct exhaustion features of T lymphocytes shape the tumor-immune microenvironment with therapeutic implication in patients with non-small-cell lung cancer
Chang Gon Kim, Gamin Kim, Kyung Hwan Kim, Seyeon Park, Seyeon Park, Sunhye Shin, Dahee Yeo, Hyo Sup Shim, Hong In Yoon, Sung Yong Park, Sung Yong Park, Sang‐Jun Ha, Hye Ryun Kim
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.