Systemic immune dysfunction in cancer patients driven by IL6 and IL8 induction of an inhibitory receptor module in peripheral CD8+T cells

Many cancer patients do not develop a durable response to the current standard of care immunotherapies despite substantial advances in targeting immune inhibitory receptors 1-5 . A potential compounding issue, which may serve as an unappreciated, dominant resistance mechanism, is an inherent systemic immune dysfunction that is often associated with advanced cancer 6-12 . Minimal response to inhibitory receptor (IR) blockade therapy and increased disease burden have been associated with peripheral CD8 + T cell dysfunction, characterized by suboptimal T cell proliferation and chronic expression of IRs (eg. Programmed Death 1 [PD1] and Lymphocyte Activation Gene 3 [LAG3]) 13, 14 . Here, we demonstrate that up to a third of cancer patients express robust intracellular LAG3 (LAG3 IC ), but not surface LAG3 (LAG3 SUR ), in peripheral CD8 + T cells compared to CD4 + T cells and regulatory T cells (T regs ). LAG3 IC is associated with: (i) expression of a LAG3 IC -dominant IR module that includes PD1 IC , NRP1 IC , CD39 IC , and TIGIT IC ; (ii) decreased CD8 + but not CD4 + T cell function that can be reversed by anti-LAG3 (and/or anti-PD1), despite limited constitutive surface IR expression; and (iii) poor disease prognosis. Systemic immune dysfunction is restricted to CD8 + T cells, including a high percentage of peripheral naïve CD8 + T cells, indicating a TCR-independent mechanism that is driven by the cytokine IL6 and the chemokine IL8. Thus, the combination of an increased LAG3-dominant IR module and elevated systemic IL6 and/or IL8 may serve as predictive biomarkers and increase the possibility that cancer patients will benefit from therapeutic combinations targeting these systemic cytokines in the setting of PD1 and/or LAG3 blockade.