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

Abstract

BackgroundReinvigoration 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.MethodsWe 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-1high, PD-1int, and PD-1neg cells). Patients were classified based on the presence or absence of discrete PD-1high CD8+ TILs. Production of effector cytokines by CD8+ TILs was measured after T-cell stimulation with or without antibodies against immune checkpoint receptors.ResultsProgressive T-cell exhaustion with marked expression of exhaustion-related markers and diminished production of effector cytokines was observed in PD-1high CD8+ TILs compared with PD-1int and PD-1neg CD8+ TILs. Patients with distinct PD-1high CD8+ TILs (PD-1high expressers) exhibited characteristics associated with a favorable anti-PD-1 response compared with those without these lymphocytes (non-PD-1high expressers). Combined inhibition of dual immune checkpoint receptors further restored effector cytokine production by CD8+ TILs following T-cell stimulation. PD-1high CD8+ T lymphocyte populations in the peripheral blood and tumors were significantly correlated.ConclusionsT-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.

Construction and evaluation of a prognostic risk model of tumor metastasis-related genes in patients with non-small cell lung cancer

“…Tumor metastasis is triggered by interactions between cancer cells and numerous stromal cell components of the tumor microenvironment, as well as by the accumulation of intrinsic changes in malignant cells [ 31 , 32 ]. Inflammation and infiltration of tumor tissue by immune cells from the host, such as tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, have been demonstrated to promote tumor development as well as invasion and metastasis [ 33 , 34 ]. Our data showed that the immune score and stromal score of the high-risk group was significantly higher than that of the low-risk group.…”

T Lymphocytes as Targets for SARS-CoV-2

“…The functional exhaustion of T lymphocytes is also commonly reported in COVID-19 patients [52,53]. This is a variant of T cell dysfunction, in which a short-term T lymphocyte hyperactivation in response to an antigen is replaced by a progressive decrease in the proliferative activity, loss of eff ector functions, expression of inhibitory receptors such as PD-1 and CTLA, and epigenetic and transcriptional reprogramming [52,53].…”

“…The functional exhaustion of T lymphocytes is also commonly reported in COVID-19 patients [52,53]. This is a variant of T cell dysfunction, in which a short-term T lymphocyte hyperactivation in response to an antigen is replaced by a progressive decrease in the proliferative activity, loss of eff ector functions, expression of inhibitory receptors such as PD-1 and CTLA, and epigenetic and transcriptional reprogramming [52,53]. The decrease in the T cell functions in COVID-19 may be partly due to their non-productive infection with SARS-CoV-2, as well as non-infectious T lymphocyte regulation associated with the direct interaction of the viral S protein with the TCR, which causes the blockade or disruption of the antigen-dependent signaling.…”

“…In addition, the virus-dependent impairment of Tregs may be related to the functional exhaustion of T lymphocytes, which prevents an eff ective antiviral response [52]. It is the violation of Treg control that can be responsible for the hyperactivation of eff ector T lymphocytes preceding their functional depletion [53].…”

Characteristics of the immune microenvironment and their clinical significance in non-small cell lung cancer patients with ALK-rearranged mutation

“…Preclinical studies have shown that PD-1 inhibitors improve the survival of mice with EGFR-driven lung cancer by enhancing T-cell function (43). Chang Gon Kim et al showed that patients with PD-1high CD8+ TILs (PD-1-high expressers) exhibited characteristics associated with a favorable anti-PD-1 response compared with those without these lymphocytes (non-PD-1high expressers) (44). Mechanistically, a low proportion of PD-1+ and CD8+ TILs co-expressed may underlie the low response rates to PD-1/PD-L1 inhibitors in EGFR-/ALKpositive NSCLC patients.…”