Immuno-oncology

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T Cell Immunotherapies Trigger Innate Immunity and Aseptic Inflammation Leading to Potent Anti-tumor and Off-targets Effects

Thursday, June 15
5:45 PM - 7:00 PM

Mobilizing the immune system to treat advanced cancers is now a clinical reality. Successful immune-based therapies that treat tumors are often accompanied by immune-related adverse events (irAE) including toxicities that can occasionally present with severe and lethal symptoms.  The primary immunotherapies currently in clinic include agents that activate T cell responses such as checkpoint blockade of inhibitory pathways and infusion of ex-vivo tumor-derived or T cell receptor (TCR)-transgenic or chimeric antigen receptor (CAR)-modified T cells.  While the beneficial and toxic effects of T cell-based immunotherapies in the clinic are being extensively explored, the precise mechanisms of tumor elimination and irAE remain the subject of intense investigation. In the present study, we treated established tumors with melanoma-specific adoptive CD4+ T cell transfer and costimulation via OX40 or checkpoint blockade with anti-CTLA-4. We found that, in spite of co-opting the adaptive immune response to treat cancer, acute local inflammation, resembling delayed-type hypersensitivity, plays a fundamental role in tumor elimination and related toxicities in a model of irAE.  While OX40 or CTLA-4 antibodies stimulated T cells are necessary for initiating a therapeutic response, activation of endogenous neutrophils constitutes an important and necessary effector mechanism of tumor destruction and irAE. Upon closer examination, we found extensive neutrophil extracellular traps (NETs) in ear pinnae of treated mice and in melanoma patients suffering from immunotherapy-induced irAE.  Our results illustrate the involvement of innate immunity in promoting tumor elimination and subsequent side effects with immunotherapies that engage T cells.  

Daniel Hirschhorn Cymerman

Ludwig Collaborative and Swim Across America laboratory, Memorial Sloan Kettering Cancer Center

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    Olivier De Hanau

    Ludwig Collaborative Laboratory, MSKCC

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      Jacob Ricca

      Ludwig Collaborative Laboratory, MSKCC

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        Billel Gasmi

        Ludwig Collaborative and Swim Across America laboratory, Memorial Sloan Kettering Cancer Center

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          Levi Mark B Mangarin

          Ludwig Collaborative Laboratory

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            Sadna Budhu

            Ludwig Collaborative and Swim Across America laboratory, Memorial Sloan Kettering Cancer Center

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              Yanyun Li

              Memorial Sloan Kettering Cancer Center

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                Czrina A Cortez

                Ludwig Collaborative Laboratory

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                  Xia Yang

                  Ludwig Collaborative Laboratory, MSKCC

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                    Hong Zhong

                    Ludwig Collaborative and Swim Across America laboratory, Memorial Sloan Kettering Cancer Center

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                      Cailian Liu

                      Ludwig Collaborative and Swim Across America laboratory, Memorial Sloan Kettering Cancer Center

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                        Roberta Zappasodi

                        Research Scholar
                        Parker Institute for Cancer Immunotherapy, Ludwig Collaborative and Swim Across America laboratory, Memorial Sloan Kettering Cancer Center

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                          Jean Albrengues

                          Postdoctoral Fellow
                          Cold Spring Harbor Laboratory

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                            Mikala Egeblad

                            Assistant Proffessor
                            Cold Spring Harbor Laboratory

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                              Jedd D. Wolchok

                              Parker Institute for Cancer Immunotherapy, Ludwig Collaborative and Swim Across America laboratory, Memorial Sloan Kettering Cancer Center

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                                Merghoub Taha

                                Assistant Member
                                Parker Institute for Cancer Immunotherapy, Ludwig Collaborative and Swim Across America laboratory, Memorial Sloan Kettering Cancer Center

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                                  T Cell Immunotherapies Trigger Innate Immunity and Aseptic Inflammation Leading to Potent Anti-tumor and Off-targets Effects



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