Innamarato et al. show that after cyclophosphamide-fludarabine (Cy/Flu) lymphodepleting chemotherapy, immunosuppressive CD11b+ myeloid cells accumulated in peripheral blood, which correlated with a decrease in tumor-specific T cell persistence and poor PFS and OS in melanoma patients. Cy/Flu lymphodepletion mobilized myeloid progenitor cells, expanded MDSCs, and increased IL-6 expression in bone marrow-derived cells in the B16 melanoma model. IL-6 blockade reduced the suppressive capacity of MDSCs, increased Fas expression, sensitized MDSCs to apoptotic signals, and enhanced ACT efficacy in vivo.
Contributed by Shishir Pant
ABSTRACT: Adoptive T cell therapy (ACT) in combination with lymphodepleting chemotherapy is an effective strategy to induce the eradication of tumors, providing long-term regression in cancer patients. Despite that lymphodepleting regimens condition the host for optimal engraftment and expansion of adoptively transferred T cells, lymphodepletion concomitantly promotes immunosuppression during the course of endogenous immune recovery. In this study, we have identified that lymphodepleting chemotherapy initiates the mobilization of hematopoietic progenitor cells that differentiate to immunosuppressive myeloid cells, leading to a dramatic increase of peripheral myeloid-derived suppressor cells (MDSCs). In melanoma and lung cancer patients, MDSCs rapidly expanded in the periphery within 1 week after completion of a lymphodepleting regimen and infusion of autologous tumor-infiltrating lymphocytes (TILs). This expansion was associated with disease progression, poor survival, and reduced TIL persistence in melanoma patients. We demonstrated that the interleukin 6 (IL-6)-driven differentiation of mobilized hematopoietic progenitor cells promoted the survival and immunosuppressive capacity of post-lymphodepletion MDSCs. Furthermore, the genetic abrogation or therapeutic inhibition of IL-6 in mouse models enhanced host survival and reduced tumor growth in mice that received ACT. Thus, the expansion of MDSCs in response to lymphodepleting chemotherapy may contribute to ACT failure, and targeting myeloid-mediated immunosuppression may support anti-tumor immune responses.
Author Info: (1) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Cancer Biology PhD Program, University of South Florida, Tampa, FL, USA. (2) Depa
Author Info: (1) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Cancer Biology PhD Program, University of South Florida, Tampa, FL, USA. (2) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (3) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (4) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (5) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Cancer Biology PhD Program, University of South Florida, Tampa, FL, USA. (6) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (7) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (8) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (9) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (10) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Department of Thoracic Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (11) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (12) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address: shari.pilon-thomas@moffitt.org.
