T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants

Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that activate multiple branches of the immune system may eliminate escape variants. Here, we show that melanoma-specific CD4 T cell therapy in combin...

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Veröffentlicht in:	Cell Jg. 186; H. 7; S. 1432
Hauptverfasser:	Hirschhorn, Daniel, Budhu, Sadna, Kraehenbuehl, Lukas, Gigoux, Mathieu, Schröder, David, Chow, Andrew, Ricca, Jacob M, Gasmi, Billel, De Henau, Olivier, Mangarin, Levi Mark B, Li, Yanyun, Hamadene, Linda, Flamar, Anne-Laure, Choi, Hyejin, Cortez, Czrina A, Liu, Cailian, Holland, Aliya, Schad, Sara, Schulze, Isabell, Betof Warner, Allison, Hollmann, Travis J, Arora, Arshi, Panageas, Katherine S, Rizzuto, Gabrielle A, Duhen, Rebekka, Weinberg, Andrew D, Spencer, Christine N, Ng, David, He, Xue-Yan, Albrengues, Jean, Redmond, David, Egeblad, Mikala, Wolchok, Jedd D, Merghoub, Taha
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 30.03.2023
Schlagworte:	Animals Antigenic Drift and Shift CTLA-4 Antigen Immunotherapy Melanoma Mice Neutrophils - pathology T-Lymphocytes - pathology OX40 neutrophil extracellular traps antigenic heterogeneity immunotherapy anti-tumor neutrophils CTLA-4 adoptive T cell therapies neutrophils tumor hetergeneity immune checkpoint blockade
ISSN:	1097-4172, 1097-4172
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Abstract	Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that activate multiple branches of the immune system may eliminate escape variants. Here, we show that melanoma-specific CD4 T cell therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate melanomas containing antigen escape variants. As expected, early on-target recognition of melanoma antigens by tumor-specific CD4 T cells was required. Surprisingly, complete tumor eradication was dependent on neutrophils and partly dependent on inducible nitric oxide synthase. In support of these findings, extensive neutrophil activation was observed in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade. Transcriptomic and flow cytometry analyses revealed a distinct anti-tumorigenic neutrophil subset present in treated mice. Our findings uncover an interplay between T cells mediating the initial anti-tumor immune response and neutrophils mediating the destruction of tumor antigen loss variants.
AbstractList	Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that activate multiple branches of the immune system may eliminate escape variants. Here, we show that melanoma-specific CD4+ T cell therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate melanomas containing antigen escape variants. As expected, early on-target recognition of melanoma antigens by tumor-specific CD4+ T cells was required. Surprisingly, complete tumor eradication was dependent on neutrophils and partly dependent on inducible nitric oxide synthase. In support of these findings, extensive neutrophil activation was observed in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade. Transcriptomic and flow cytometry analyses revealed a distinct anti-tumorigenic neutrophil subset present in treated mice. Our findings uncover an interplay between T cells mediating the initial anti-tumor immune response and neutrophils mediating the destruction of tumor antigen loss variants.Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that activate multiple branches of the immune system may eliminate escape variants. Here, we show that melanoma-specific CD4+ T cell therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate melanomas containing antigen escape variants. As expected, early on-target recognition of melanoma antigens by tumor-specific CD4+ T cells was required. Surprisingly, complete tumor eradication was dependent on neutrophils and partly dependent on inducible nitric oxide synthase. In support of these findings, extensive neutrophil activation was observed in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade. Transcriptomic and flow cytometry analyses revealed a distinct anti-tumorigenic neutrophil subset present in treated mice. Our findings uncover an interplay between T cells mediating the initial anti-tumor immune response and neutrophils mediating the destruction of tumor antigen loss variants. Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that activate multiple branches of the immune system may eliminate escape variants. Here, we show that melanoma-specific CD4 T cell therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate melanomas containing antigen escape variants. As expected, early on-target recognition of melanoma antigens by tumor-specific CD4 T cells was required. Surprisingly, complete tumor eradication was dependent on neutrophils and partly dependent on inducible nitric oxide synthase. In support of these findings, extensive neutrophil activation was observed in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade. Transcriptomic and flow cytometry analyses revealed a distinct anti-tumorigenic neutrophil subset present in treated mice. Our findings uncover an interplay between T cells mediating the initial anti-tumor immune response and neutrophils mediating the destruction of tumor antigen loss variants.
Author	Holland, Aliya Rizzuto, Gabrielle A Hamadene, Linda Hirschhorn, Daniel Cortez, Czrina A Ricca, Jacob M Arora, Arshi Choi, Hyejin Hollmann, Travis J Gigoux, Mathieu He, Xue-Yan Spencer, Christine N Gasmi, Billel Li, Yanyun Albrengues, Jean Mangarin, Levi Mark B Chow, Andrew Duhen, Rebekka De Henau, Olivier Betof Warner, Allison Kraehenbuehl, Lukas Flamar, Anne-Laure Ng, David Liu, Cailian Merghoub, Taha Budhu, Sadna Schad, Sara Schulze, Isabell Redmond, David Wolchok, Jedd D Schröder, David Panageas, Katherine S Egeblad, Mikala Weinberg, Andrew D
Author_xml	– sequence: 1 givenname: Daniel surname: Hirschhorn fullname: Hirschhorn, Daniel organization: Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY, USA – sequence: 2 givenname: Sadna surname: Budhu fullname: Budhu, Sadna organization: Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY, USA – sequence: 3 givenname: Lukas surname: Kraehenbuehl fullname: Kraehenbuehl, Lukas organization: Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY, USA; Department of Dermatology, University Hospital Zurich, Zurich, Switzerland – sequence: 4 givenname: Mathieu surname: Gigoux fullname: Gigoux, Mathieu organization: Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA – sequence: 5 givenname: David surname: Schröder fullname: Schröder, David organization: Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA – sequence: 6 givenname: Andrew surname: Chow fullname: Chow, Andrew organization: Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA – sequence: 7 givenname: Jacob M surname: Ricca fullname: Ricca, Jacob M organization: Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA – sequence: 8 givenname: Billel surname: Gasmi fullname: Gasmi, Billel organization: Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA – sequence: 9 givenname: Olivier surname: De Henau fullname: De Henau, Olivier organization: Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA – sequence: 10 givenname: Levi Mark B surname: Mangarin fullname: Mangarin, Levi Mark B organization: Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA; 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Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA – sequence: 26 givenname: Andrew D surname: Weinberg fullname: Weinberg, Andrew D organization: Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA – sequence: 27 givenname: Christine N surname: Spencer fullname: Spencer, Christine N organization: Department of Informatics, Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA – sequence: 28 givenname: David surname: Ng fullname: Ng, David organization: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA – sequence: 29 givenname: Xue-Yan surname: He fullname: He, Xue-Yan organization: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA – sequence: 30 givenname: Jean surname: Albrengues fullname: Albrengues, Jean organization: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA – sequence: 31 givenname: David surname: Redmond fullname: Redmond, David organization: Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY, USA – sequence: 32 givenname: Mikala surname: Egeblad fullname: Egeblad, Mikala organization: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA – sequence: 33 givenname: Jedd D surname: Wolchok fullname: Wolchok, Jedd D organization: Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY, USA; Department of Medicine and Graduate Schools, Weill Cornell Medicine, New York, NY, USA – sequence: 34 givenname: Taha surname: Merghoub fullname: Merghoub, Taha email: tmerghoub@med.cornell.edu organization: Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY, USA; Department of Medicine and Graduate Schools, Weill Cornell Medicine, New York, NY, USA. Electronic address: tmerghoub@med.cornell.edu
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Keywords	OX40 neutrophil extracellular traps antigenic heterogeneity immunotherapy anti-tumor neutrophils CTLA-4 adoptive T cell therapies neutrophils tumor hetergeneity immune checkpoint blockade
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Snippet	Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that... Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that...
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SubjectTerms	Animals Antigenic Drift and Shift CTLA-4 Antigen Immunotherapy Melanoma Mice Neutrophils - pathology T-Lymphocytes - pathology
Title	T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants
URI	https://www.ncbi.nlm.nih.gov/pubmed/37001503 https://www.proquest.com/docview/2793989290
Volume	186
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