UC San Diego

Aneuploidy, aberrant chromosome numbers, is a chromosome alteration that is associated with poor prognosis and outcome in cancer. However, the exact role aneuploidy plays in cancer progression and local immune cell regulation are a matter of debate. Here we investigate the hypothesis that aneuploidy in cancer cells triggers an ER stress that will be transmitted to T cell, ultimately driving their dysfunction. We found that the conditioned medium (CM) of aneuploid murine B16.F10 and human SKOV3 cancer cells caused diminished Interferon-gamma (IFNG) and Granzyme B (GzmB) expression in T cells activated by anti-CD3/CD28 stimulation. However, the induction of aneuploidy in cancer cells did not result in UPR elevated enough to enable the transmission of UPR phenotype in T cells. T cells with diminished cytokine expression in response to aneuploid CM did not have an increase in UPR gene expression and the addition of UPR inhibitors could not restore IFNG or Granzyme expression. In fact, the induction of UPR, both through chemical means and transmissible ER stress factors, enhanced the function and activation of T cells rather than impairing their function. Finally, accumulating evidence indicates that glucose-restriction can contribute to the loss of T cell effector function by repressing EZH2, a subunit of Polycomb Repressive Complex 2 (PRC2). T cells made dysfunctional by aneuploid CM had significantly lower EZH2 expression which positively correlated with IFNG. However, addition of glucose to reactivate EZH2-mediate glucose metabolism only partially restored IFNG production in T cells. A provisional conclusion is that aneuploidy in cancer cells can cause T cell dysfunction in a cell-nonautonomous manner, but the mechanism behind it does not seem to depend on ER stress and glucose deprivation only provides a partial explanation. Further investigation is still needed to fully understand the molecular mechanism by which aneuploid CM impairs T cell immunity.