Homeostatic Dysregulation of Systemic CD8+T Cell Compartment in Lung Cancer Patients

Abstract

AbstractCancer adapts various resistance mechanisms to counteract CD8+T cell attacks. While this suppression of antigen-specific CD8+T cells is common within the tumor microenvironment, little is known about how tumors affect CD8+T cells systemically. Here we show a new link between tumor-associated homeostatic dysregulation and uncontrolled differentiation of peripheral blood CD8+T cells. These CD8+T cells exhibited progressive alterations indicative of diminished quiescence, increased spontaneous activation, and more-differentiated proliferation-incompetent effector cells. This phenomenon was not limited to tumor-reactive cells but broadly applicable to non-specific cells, correlating with poor clinical responses to immune checkpoint inhibitor therapy. These findings provide a new mechanism by which cancer impairs CD8+T cells by dysregulating the homeostasis of systemic CD8+T cell populations.One-Sentence SummaryCancer-associated homeostatic dysregulation accelerates uncontrolled differentiation of systemic CD8+T cells.