878 T cell immunotherapies recruit and activate neutrophils to eliminate tumor antigen escape variants
BackgroundThe immune system eliminates cancers in the early stages of malignant transformation. However, the presence of immune cells exerts selective pressure on tumors, which can result in tumor editing, leading to the development of immune escape variants. A common occurrence in cancers is the lo...
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| Vydáno v: | Journal for immunotherapy of cancer Ročník 11; číslo Suppl 1; s. A978 |
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| Jazyk: | angličtina |
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BMJ Publishing Group Ltd
01.11.2023
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| ISSN: | 2051-1426 |
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| Abstract | BackgroundThe immune system eliminates cancers in the early stages of malignant transformation. However, the presence of immune cells exerts selective pressure on tumors, which can result in tumor editing, leading to the development of immune escape variants. A common occurrence in cancers is the loss of antigenic protein expression on tumor cells, which creates antigenic heterogeneity and makes tumors resistant to immunotherapies such as adoptive cell therapies. Consequently, it is necessary to study and engage multiple components of the immune system in immunotherapeutic interventions to effectively eradicate heterogeneous tumors.MethodsThis study aimed to assess the efficacy of a combination therapy involving CD4+ T cells recognizing the melanoma antigen Trp1 in conjunction with either OX40 co-stimulation or CTLA-4 blockade (ICB) for eradicating advanced melanomas containing antigen escape variants in preclinical mouse models.ResultsThe combination therapy successfully eliminated antigen-loss variant clones in a preclinical mouse model of melanoma with heterogeneous Trp1 expression. Mechanistically, tumors from treated mice exhibited significant infiltration of activated neutrophils, which was also observed in cancer patients following ICB therapy. Depletion of neutrophils in our preclinical melanoma model of antigenic heterogeneity abolished the therapeutic efficacy of the combination treatment. Our findings revealed the importance of inducible nitric oxide synthase in neutrophil-mediated elimination of escape variants. Furthermore, neutrophils derived from tumors of treated mice exhibited a distinct transcriptomic and protein surface signature associated with anti-tumorigenic properties. This anti-tumorigenic neutrophil signature was also observed in tumors from melanoma patients treated with ICB that experienced survival benefits.ConclusionsOur findings demonstrate the interplay between T cells, which initiate the anti-tumor immune response, and neutrophils, which contribute to the elimination of tumor antigen loss variants in later stages. These insights underscore the potential of combined therapies in overcoming clonal escape variants in melanoma and provide valuable information on the role of neutrophils in tumor eradication when employing T cell immunotherapies.Ethics ApprovalAll tissues collected at MSKCC following study protocol approval by the MSKCC Institutional Review Board. Informed consent was obtained for all patients. The study was in strict compliance with all institutional ethical regulations. |
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| AbstractList | BackgroundThe immune system eliminates cancers in the early stages of malignant transformation. However, the presence of immune cells exerts selective pressure on tumors, which can result in tumor editing, leading to the development of immune escape variants. A common occurrence in cancers is the loss of antigenic protein expression on tumor cells, which creates antigenic heterogeneity and makes tumors resistant to immunotherapies such as adoptive cell therapies. Consequently, it is necessary to study and engage multiple components of the immune system in immunotherapeutic interventions to effectively eradicate heterogeneous tumors.MethodsThis study aimed to assess the efficacy of a combination therapy involving CD4+ T cells recognizing the melanoma antigen Trp1 in conjunction with either OX40 co-stimulation or CTLA-4 blockade (ICB) for eradicating advanced melanomas containing antigen escape variants in preclinical mouse models.ResultsThe combination therapy successfully eliminated antigen-loss variant clones in a preclinical mouse model of melanoma with heterogeneous Trp1 expression. Mechanistically, tumors from treated mice exhibited significant infiltration of activated neutrophils, which was also observed in cancer patients following ICB therapy. Depletion of neutrophils in our preclinical melanoma model of antigenic heterogeneity abolished the therapeutic efficacy of the combination treatment. Our findings revealed the importance of inducible nitric oxide synthase in neutrophil-mediated elimination of escape variants. Furthermore, neutrophils derived from tumors of treated mice exhibited a distinct transcriptomic and protein surface signature associated with anti-tumorigenic properties. This anti-tumorigenic neutrophil signature was also observed in tumors from melanoma patients treated with ICB that experienced survival benefits.ConclusionsOur findings demonstrate the interplay between T cells, which initiate the anti-tumor immune response, and neutrophils, which contribute to the elimination of tumor antigen loss variants in later stages. These insights underscore the potential of combined therapies in overcoming clonal escape variants in melanoma and provide valuable information on the role of neutrophils in tumor eradication when employing T cell immunotherapies.Ethics ApprovalAll tissues collected at MSKCC following study protocol approval by the MSKCC Institutional Review Board. Informed consent was obtained for all patients. The study was in strict compliance with all institutional ethical regulations. |
| Author | Holland, Aliya Rizzuto, Gabrielle A Hamadene, Linda Hirschhorn, Daniel Cortez, Czrina A Ricca, Jacob M Arora, Arshi Gigoux, Mathieu He, Xue-Yan Choi, Heyjin Spencer, Christine N Gasmi, Billel Li, Yanyun Warner, Allison Betof Albrengues, Jean Mangarin, Levi Mark B Chow, Andrew Duhen, Rebekka De Henau, Olivier Hollmann, Travis 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: Weill Cornell Medical and Graduate Schools, New York, New York, USA – sequence: 2 givenname: Sadna surname: Budhu fullname: Budhu, Sadna organization: Weill Cornell Medical and Graduate Schools, New York, New York, USA – sequence: 3 givenname: Lukas surname: Kraehenbuehl fullname: Kraehenbuehl, Lukas organization: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland – sequence: 4 givenname: Mathieu surname: Gigoux fullname: Gigoux, Mathieu organization: Weill Cornell Medical and Graduate Schools, New York, New York, USA – sequence: 5 givenname: David surname: Schröder fullname: Schröder, David organization: Weill Cornell Medical and Graduate Schools, New York, New York, USA – sequence: 6 givenname: Andrew surname: Chow fullname: Chow, Andrew organization: Weill Cornell Medical and Graduate Schools, New York, New York, USA – sequence: 7 givenname: Jacob M surname: Ricca fullname: Ricca, Jacob M organization: Weill Cornell Medical and Graduate Schools, New York, New York, USA – sequence: 8 givenname: Billel surname: Gasmi fullname: Gasmi, Billel organization: Weill Cornell Medical and Graduate Schools, New York, New York, USA – sequence: 9 givenname: Olivier surname: De Henau fullname: De Henau, Olivier organization: Weill Cornell Medical and Graduate Schools, New York, New York, USA – sequence: 10 givenname: Levi Mark B surname: Mangarin fullname: Mangarin, Levi Mark B organization: Weill Cornell Medical and Graduate Schools, New York, New York, USA – sequence: 11 givenname: Yanyun surname: Li fullname: Li, Yanyun organization: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA – sequence: 12 givenname: Anne-Laure surname: Flamar fullname: Flamar, Anne-Laure organization: Weill Cornell Medical and Graduate Schools, New York, New York, USA – sequence: 13 givenname: Heyjin surname: Choi fullname: Choi, Heyjin organization: Weill Cornell Medical and Graduate Schools, New York, New York, USA – sequence: 14 givenname: Czrina A surname: Cortez fullname: Cortez, Czrina A organization: Weill Cornell Medical and Graduate Schools, New York, New York, USA – sequence: 15 givenname: Cailian surname: Liu fullname: Liu, Cailian organization: Weill Cornell Medical and Graduate Schools, New York, New York, USA – sequence: 16 givenname: Aliya surname: Holland fullname: Holland, Aliya organization: Weill Cornell Medical and Graduate Schools, New York, New York, USA – sequence: 17 givenname: Sara surname: Schad fullname: Schad, Sara organization: Weill Cornell Medical and Graduate Schools, New York, New York, USA – sequence: 18 givenname: Isabell surname: Schulze fullname: Schulze, Isabell organization: Weill Cornell Medical and Graduate Schools, New York, New York, USA – sequence: 19 givenname: Linda surname: Hamadene fullname: Hamadene, Linda organization: Weill Cornell Medical and Graduate Schools, New York, New York, USA – sequence: 20 givenname: Allison Betof surname: Warner fullname: Warner, Allison Betof organization: Weill Cornell Medical and Graduate Schools, New York, New York, USA – sequence: 21 givenname: Travis surname: Hollmann fullname: Hollmann, Travis organization: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA – sequence: 22 givenname: Arshi surname: Arora fullname: Arora, Arshi organization: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, USA – sequence: 23 givenname: Katherine S surname: Panageas fullname: Panageas, Katherine S organization: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, USA – sequence: 24 givenname: Rebekka surname: Duhen fullname: Duhen, Rebekka organization: Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA – sequence: 25 givenname: Andrew D surname: Weinberg fullname: Weinberg, Andrew D organization: Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA – sequence: 26 givenname: Gabrielle A surname: Rizzuto fullname: Rizzuto, Gabrielle A organization: Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA – sequence: 27 givenname: Christine N surname: Spencer fullname: Spencer, Christine N organization: Department of Informatics, Parker Institute for Cancer Immunotherapy, San Francisco, California, USA – sequence: 28 givenname: David surname: Ng fullname: Ng, David organization: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA – sequence: 29 givenname: Xue-Yan surname: He fullname: He, Xue-Yan organization: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA – sequence: 30 givenname: Jean surname: Albrengues fullname: Albrengues, Jean organization: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 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, New York, USA – sequence: 33 givenname: Jedd D surname: Wolchok fullname: Wolchok, Jedd D organization: Weill Cornell Medical and Graduate Schools, New York, New York, USA – sequence: 34 givenname: Taha surname: Merghoub fullname: Merghoub, Taha organization: Weill Cornell Medical and Graduate Schools, New York, New York, USA |
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| Snippet | BackgroundThe immune system eliminates cancers in the early stages of malignant transformation. However, the presence of immune cells exerts selective pressure... |
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| SubjectTerms | Antigens Immune system Immunotherapy Melanoma Neutrophils Regular and Young Investigator Award Abstracts Tumors |
| Title | 878 T cell immunotherapies recruit and activate neutrophils to eliminate tumor antigen escape variants |
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