CD137 Identifies a Population of Regulatory T Cells That Inhibit Anti-Tumor Immune Responses In Adoptive Immunotherapy

Adoptive immunotherapy is a promising novel approach to the treatment of cancer. However, clinical translation of adoptively transferred CD4 T cells is limited by cotransfer of an inhibitory population of regulatory CD4 T cells (T_regs). We identified a method of isolating viable antitumor CD4 T cells while excluding T_regs based on two surface markers—CD44 and CD137.

We have developed a model for adoptive cell therapy of lymphoma whereby anti-tumor T cells are generated in vivo through vaccination with a CpG-loaded whole cell vaccine (CpG/H11). These vaccine-induced cells can protect from lethal tumor challenge when isolated and transferred into lethally irradiated, syngeneic recipient mice. We investigated the subsets of T cells involved in the anti-tumor response through a combination of in vitro and in vivo assays.

Adoptive transfer of CD137^negCD44^hi CD4 T cells, but not other sub-populations, provided protection from B cell lymphoma. We demonstrate that the population of CD137^posCD44^hi CD4 T cells consists primarily of activated T_regs. In vitro, these CD137^pos cells suppressed the proliferation of effector cells in a contact-dependent manner. We observed that this CD137^pos T_reg population persisted following adoptive transfer and maintained expression of FoxP3 as well as CD137. Moreover, the addition of CD137^posCD44^hi CD4 cells to CD137^negCD44^hi CD4 cells suppressed the antitumor immune response. In the presence of CD137^posCD44^hi CD4 T cells, homing of other T cell populations to tumor sites was disrupted. These results suggest that CD137 expression on CD4 T cells defines a population of activated T_regs that prevent antitumor immune responses.

Our findings identify two surface markers that can be used to facilitate the enrichment of anti-tumor CD4 T cells while depleting an inhibitory T_reg population. This approach has direct applicability to clinical trials for patients with lymphoma.

No relevant conflicts of interest to declare.