IL-6 dependent myeloid derived suppressor cells induced by lymphodepleting chemotherapy limits the efficacy of adoptive T cell therapy
Innamarato PP1,2, Kodumudi K1, Morse J1, Sarnaik A1, Pilon-Thomas S1
1Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA; 2Cancer Biology PhD Program, University of South Florida, Tampa, Florida, USA
Lymphodepleting chemotherapy administered before adoptive T cell therapy (ACT) can enhance anti-tumor immune responses by increasing availability of homeostatic cytokines. However, the induction of lymphopenia by nonmyeloablative chemotherapy also prompts the rapid reconstitution of highly immunosuppressive myeloid derived suppressor cells (MDSCs) that inhibit anti-tumor responses elicited by adoptively transferred T cells. We hypothesize that impairing the suppressive functions of lymphodepletion-induced MDSCs will enhance the efficacy of ACT. Seven days after administration of lymphodepleting agents, cyclophosphamide and fludarabine, the frequency of splenic-MDSCs is increased by 2.5 fold (p<0.05) compared to tumor-bearing untreated mice. Similarly, MDSCs are elevated in melanoma patients receiving ACT with tumor infiltrating lymphocytes (TIL) enrolled on our clinical trial. Plasma levels of IL-6 are elevated in patients immediately after infusion of TIL and administration of lymphodepleting chemotherapy. To examine the role of IL-6 on the function of lymphodepletion-induced MDSCs, we examined the suppressive capacity of MDSCs derived from IL-6-/- mice and IL-6R knockout mice specific to the myeloid lineage (IL-6RM-KO). We found that MDSCs derived from IL-6-/- and IL-6RM-KO lymphodepleted mice lost the ability to suppress T cell proliferation and interferon-gamma production. In contrast, MDSCs from IL-6-/- and IL-6RM-KO untreated mice were equally as suppressive as MDSCs from WT mice, indicating that the suppressive capacity of MDSCs induced by lymphodepleting chemotherapy is dependent on IL-6. Furthermore, in an ACT model, B16 tumors were smaller in IL-6-/- mice (52mm^2) and IL-6RM-KO mice (123mm^2) than WT mice (341mm^2), 47 days after T cell infusion. The reduction in tumor size and increased survival rate indicates that IL-6 signaling in the myeloid lineage restricts the efficacy of ACT. Together, these results provide evidence that targeting the IL-6 axis can enhance the therapeutic efficacy of ACT through the reduction of myeloid-mediated immunosuppression.