부산대학교 도서관

Keywords immunotherapy; neutrophils; OX40; adoptive T cell therapies; anti-tumor neutrophils; immune checkpoint blockade; CTLA-4; neutrophil extracellular traps; tumor hetergeneity; antigenic heterogeneity Highlights * T cell immunotherapies can eliminate antigenically heterogeneous tumors * Neutrophils are recruited and are responsible for killing antigen loss variants * Anti-tumorigenic neutrophils display a distinct genotype and phenotype * Neutrophil activation is observed in patients treated with T cell immunotherapies Summary 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.sup.+ 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.sup.+ 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 Affiliation: (1) Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA (2) Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY, USA (3) Department of Dermatology, University Hospital Zurich, Zurich, Switzerland (4) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA (5) Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA (6) Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA (7) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA (8) Department of Informatics, Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA (9) Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA (10) Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY, USA (11) Department of Medicine and Graduate Schools, Weill Cornell Medicine, New York, NY, USA * Corresponding author Article History: Received 14 February 2022; Revised 11 October 2022; Accepted 3 March 2023 (miscellaneous) Published: March 30, 2023 (footnote)12 Senior author (footnote)13 These authors contributed equally (footnote)14 Lead contact Byline: Daniel Hirschhorn (1,2), Sadna Budhu (1,2), Lukas Kraehenbuehl (1,2,3), Mathieu Gigoux (1), David Schröder (1), Andrew Chow (1), Jacob M. Ricca (1), Billel Gasmi (1), Olivier De Henau (1), Levi Mark B. Mangarin (1,2), Yanyun Li (4), Linda Hamadene (1,2), Anne-Laure Flamar (1), Hyejin Choi (1), Czrina A. Cortez (1), Cailian Liu (1,2), Aliya Holland (1), Sara Schad (1), Isabell Schulze (1,2), Allison Betof Warner (1), Travis J. Hollmann (4), Arshi Arora (5), Katherine S. Panageas (5), Gabrielle A. Rizzuto (6), Rebekka Duhen (7), Andrew D. Weinberg (7), Christine N. Spencer (8), David Ng (9), Xue-Yan He (9), Jean Albrengues (9), David Redmond (10), Mikala Egeblad (9), Jedd D. Wolchok (1,2,11,12,13), Taha Merghoub [tmerghoub@med.cornell.edu] (1,2,11,12,13,14,*)