Modulation of CD8 + memory stem T cell activity and glycogen synthase kinase 3β inhibition enhances anti-tumoral immunity in gastric cancer

The potential contributions of CD8⁺ memory stem T cells to anti-tumor immunity and immunotherapy responses in gastric cancer has not been demonstrated. We found that CD8⁺ memory stem T cell frequencies were increased in the peripheral blood of gastric cancer patients compared to healthy donors and declined in frequency with disease progression. Despite minimal in vitro cytotoxic activity, the adoptive transfer of CD8⁺ memory stem T cells into Rag1^-/- tumor bearing mice enhanced tumor regression compared to CD8⁺ central or effector memory T cell counterparts. This effect was associated with an increase in splenic, draining lymph node and tumor infiltrating CD8⁺ T cell numbers and the development of an altered CD8⁺ T cell phenotype not seen during homeostasis. GSK-3β inhibition is known to promote memory stem T cell accumulation by arresting effector T cell differentiation in vivo. Surprisingly however, GSK-3β inhibition conversely increased the cytotoxic capacity of CD8⁺ memory stem T cells in vitro, and this was associated with the induction of effector T cell-associated effector proteins including FasL. Finally, FasL neutralization following GSK-3β inhibition directly attenuated the anti-tumoral capacity of CD8⁺ memory stem T cells both in vitro and in vivo. Altogether, our findings identify the therapeutic potential of modulating CD8⁺ memory stem T cells for improved anti-tumoral responses against gastric cancer.