99 T cell immunotherapies trigger neutrophil activation to eliminate tumor antigen escape variants

BackgroundTargeted immune-based therapies such as adoptive T cell transfer (ACT) are often ineffective because tumors evolve over time and under selective pressure display antigen loss variant clones. A classic example in melanoma is de-differentiation and loss of expression of antigenic proteins. T...

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Published in:Journal for immunotherapy of cancer Vol. 9; no. Suppl 2; p. A108
Main Authors: Hirschhorn, Daniel, Budhu, Sadna, Schröder, David, kraehenbuehl, Lukas, Flammar, Anne-Laurent, Chow, Andrew, Schulze, Isabell, Schad, Sara, Ricca, Jacob, Gasmi, Billel, Henau, Olivier De, Mangarin, Levi, Redmond, David, Cortez, Czrina, Liu, Cailian, Holland, Aliya, Gigoux, Mathieu, Arora, Asrhi, Panageas, Katherine, Rizzuto, Gabrielle, Albrengues, Jean, Egeblad, Mikala, Wolchok, Jedd, Merghoub, Taha
Format: Journal Article
Language:English
Published: London BMJ Publishing Group Ltd 01.11.2021
BMJ Publishing Group LTD
BMJ Publishing Group
Subjects:
Antigens
Immunotherapy
Melanoma
Neutrophils
Regular and Young Investigator Award Abstracts
Tumors
ISSN:2051-1426
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Abstract BackgroundTargeted immune-based therapies such as adoptive T cell transfer (ACT) are often ineffective because tumors evolve over time and under selective pressure display antigen loss variant clones. A classic example in melanoma is de-differentiation and loss of expression of antigenic proteins. Therapies that activate multiple branches of the immune system may eliminate such escape variantsMethodsHere we show that melanoma-specific CD4+ ACT therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate large melanoma tumors with clonal escape variants.ResultsEarly on-target recognition of melanoma antigens by adoptively transferred tumor-specific CD4+ T cells was required. Surprisingly, however, complete tumor eradication was partially dependent on neutrophils. Supporting these findings, extensive neutrophil activation and neutrophil extracellular traps were found in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade.ConclusionsOur findings uncover a novel interplay between T cells mediating the initial tumor- and tissue-specific immune response, and neutrophils mediating tumor destruction of antigen loss variants.Ethics ApprovalAll tissues were collected at MSKCC following study protocol approval by the MSKCC Institutional Review Board. All mouse procedures were performed in accordance with institutional protocol guidelines at Memorial Sloan-Kettering Cancer Center (MSKCC) under an approved protocol.
AbstractList BackgroundTargeted immune-based therapies such as adoptive T cell transfer (ACT) are often ineffective because tumors evolve over time and under selective pressure display antigen loss variant clones. A classic example in melanoma is de-differentiation and loss of expression of antigenic proteins. Therapies that activate multiple branches of the immune system may eliminate such escape variantsMethodsHere we show that melanoma-specific CD4+ ACT therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate large melanoma tumors with clonal escape variants.ResultsEarly on-target recognition of melanoma antigens by adoptively transferred tumor-specific CD4+ T cells was required. Surprisingly, however, complete tumor eradication was partially dependent on neutrophils. Supporting these findings, extensive neutrophil activation and neutrophil extracellular traps were found in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade.ConclusionsOur findings uncover a novel interplay between T cells mediating the initial tumor- and tissue-specific immune response, and neutrophils mediating tumor destruction of antigen loss variants.Ethics ApprovalAll tissues were collected at MSKCC following study protocol approval by the MSKCC Institutional Review Board. All mouse procedures were performed in accordance with institutional protocol guidelines at Memorial Sloan-Kettering Cancer Center (MSKCC) under an approved protocol.
Author Holland, Aliya
Hirschhorn, Daniel
Mangarin, Levi
Flammar, Anne-Laurent
Liu, Cailian
Panageas, Katherine
Arora, Asrhi
Merghoub, Taha
Ricca, Jacob
Wolchok, Jedd
Budhu, Sadna
Cortez, Czrina
Gigoux, Mathieu
Schad, Sara
Henau, Olivier De
kraehenbuehl, Lukas
Schulze, Isabell
Redmond, David
Gasmi, Billel
Schröder, David
Rizzuto, Gabrielle
Albrengues, Jean
Egeblad, Mikala
Chow, Andrew
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Copyright Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.
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Snippet BackgroundTargeted immune-based therapies such as adoptive T cell transfer (ACT) are often ineffective because tumors evolve over time and under selective...
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SubjectTerms Antigens
Immunotherapy
Melanoma
Neutrophils
Regular and Young Investigator Award Abstracts
Tumors
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Title 99 T cell immunotherapies trigger neutrophil activation to eliminate tumor antigen escape variants
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