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Reactive Myelopoiesis Triggered by Lymphodepleting Chemotherapy Limits the Efficacy of Adoptive T Cell Therapy.
Mol Ther. 2020 Jun 24 [Online ahead of print]MT

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.

Authors+Show Affiliations

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.Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.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.Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.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.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.Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address: shari.pilon-thomas@moffitt.org.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32615068

Citation

Innamarato, Patrick, et al. "Reactive Myelopoiesis Triggered By Lymphodepleting Chemotherapy Limits the Efficacy of Adoptive T Cell Therapy." Molecular Therapy : the Journal of the American Society of Gene Therapy, 2020.
Innamarato P, Kodumudi K, Asby S, et al. Reactive Myelopoiesis Triggered by Lymphodepleting Chemotherapy Limits the Efficacy of Adoptive T Cell Therapy. Mol Ther. 2020.
Innamarato, P., Kodumudi, K., Asby, S., Schachner, B., Hall, M., Mackay, A., Wiener, D., Beatty, M., Nagle, L., Creelan, B. C., Sarnaik, A. A., & Pilon-Thomas, S. (2020). Reactive Myelopoiesis Triggered by Lymphodepleting Chemotherapy Limits the Efficacy of Adoptive T Cell Therapy. Molecular Therapy : the Journal of the American Society of Gene Therapy. https://doi.org/10.1016/j.ymthe.2020.06.025
Innamarato P, et al. Reactive Myelopoiesis Triggered By Lymphodepleting Chemotherapy Limits the Efficacy of Adoptive T Cell Therapy. Mol Ther. 2020 Jun 24; PubMed PMID: 32615068.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reactive Myelopoiesis Triggered by Lymphodepleting Chemotherapy Limits the Efficacy of Adoptive T Cell Therapy. AU - Innamarato,Patrick, AU - Kodumudi,Krithika, AU - Asby,Sarah, AU - Schachner,Benjamin, AU - Hall,MacLean, AU - Mackay,Amy, AU - Wiener,Doris, AU - Beatty,Matthew, AU - Nagle,Luz, AU - Creelan,Ben C, AU - Sarnaik,Amod A, AU - Pilon-Thomas,Shari, Y1 - 2020/06/24/ PY - 2020/04/21/received PY - 2020/06/01/revised PY - 2020/06/18/accepted PY - 2020/7/3/entrez PY - 2020/7/3/pubmed PY - 2020/7/3/medline KW - adoptive cell therapy KW - cancer immunotherapy KW - cyclophosphamide KW - fludarabine KW - lymphodepletion KW - myeloid derived suppressor cells JF - Molecular therapy : the journal of the American Society of Gene Therapy JO - Mol. Ther. N2 - 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. SN - 1525-0024 UR - https://www.unboundmedicine.com/medline/citation/32615068/Reactive_Myelopoiesis_Triggered_by_Lymphodepleting_Chemotherapy_Limits_the_Efficacy_of_Adoptive_T_Cell_Therapy L2 - https://linkinghub.elsevier.com/retrieve/pii/S1525-0016(20)30315-4 DB - PRIME DP - Unbound Medicine ER -
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