IL-6, IL-8 drive LAG3/PD1 immune suppression on effector and naïve, peripheral blood CD8+ T cells in cancer patients

Abstract

Abstract Cancer patients off therapy and with normal white blood cell counts are often at greater risk for infections, immune dysregulation, progressive disease or reactivation of viral infections. However, the exact mechanism of this systemic immunosuppression in cancer patients is not fully understood. We hypothesize that cancer patients may have systemic immune suppression via cytokine-driven IR expression in all CD8+ T cells subsets, including naïve cells. PBL were obtained from healthy donors and treatment-naïve NSCLC, HNSCC, and melanoma patients. IR (i.e. LAG3, PD1, CTLA4, etc) expression was assessed on CD8+ T cells, CD4+ T cells, and regulatory T cells. Plasma cytokine concentrations were compared by Luminex. Autologous micro-stimulation assays were performed on peripheral CD8+ or CD4+ T cells with antigen presenting cells plus or minus IR blockade. CD8+ T cells, including naive CD8+ T cells, from cancer patient PBL contain elevated total LAG3 expression which correlated with worse state, worse survival, and elevated expression of other IRs. Further, CD8+ T cells from these patients had decreased proliferation, which was rescued with the addition of anti-LAG3 or anti-PD1. Plasma from these patients had significantly elevated levels of cytokines that can signal via STAT3 (i.e. IL-6, IL-8), which were independently found to increase total IR expression in healthy donor, naïve CD8+ T cells. Patients with cancer have systemic elevations IL-6 and IL-8 leading to increased IR expression in naïve, peripheral CD8+ T cells making them poised for exhaustion even before TCR binding. These findings suggest that cytokine combined with IR blockade may play a role in reversing PD1 blockade resistance.