Progressive accumulation of circulating CD27CD28 effector/memory CD8 T cells in patients with lung cancer blunts responses to immune checkpoint inhibitor therapy.

Suppression of tumor-reactive CD8 T cells is common within the tumor microenvironment. However, little is known about how tumors systemically affect the overall CD8 T cell compartment. Here we demonstrate that peripheral blood CD8 T cells from patients with lung cancer showed altered compositions particularly within CD45RACCR7 effector memory subpopulation. Specifically, patients with lung cancer exhibited increased frequency of more differentiated effector memory cells, which are less susceptible to T cell-receptor-induced proliferation. Further analysis using single-cell RNA sequencing revealed that these alterations were correlated with reduced quiescence and increased spontaneous activation at a systemic level, indicative of homeostatic dysregulation of the entire CD8 T cell population. This phenomenon was found to be correlated with a poor clinical response to immune checkpoint inhibitor therapy across four independent cohorts, consisting of a total of 224 patients with lung cancer. These findings suggest that lung cancers continue to counteract potentially tumor-reactive CD8 T cells by inducing homeostatic dysregulation of the entire CD8 T cell compartment systematically.