T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants Journal Article
| Authors: | Hirschhorn, D.; Budhu, S.; Kraehenbuehl, L.; Gigoux, M.; Schröder, D.; Chow, A.; Ricca, J. M.; Gasmi, B.; De Henau, O.; Mangarin, L. M. B.; Li, Y.; Hamadene, L.; Flamar, A. L.; Choi, H.; Cortez, C. A.; Liu, C.; Holland, A.; Schad, S.; Schulze, I.; Betof Warner, A.; Hollmann, T. J.; Arora, A.; Panageas, K. S.; Rizzuto, G. A.; Duhen, R.; Weinberg, A. D.; Spencer, C. N.; Ng, D.; He, X. Y.; Albrengues, J.; Redmond, D.; Egeblad, M.; Wolchok, J. D.; Merghoub, T. |
| Article Title: | T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants |
| 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. © 2023 Elsevier Inc. |
| Keywords: | clinical article; controlled study; human tissue; human cell; nonhuman; cancer patient; flow cytometry; t lymphocyte; t-lymphocytes; animal cell; mouse; animal; animals; mice; animal tissue; ipilimumab; cancer immunotherapy; melanoma; animal experiment; animal model; cohort analysis; tumor biopsy; tumor regression; pathology; transcriptomics; neutrophil; immunotherapy; antigen recognition; cd4+ t lymphocyte; cell therapy; adoptive transfer; innate immunity; neutrophils; melanoma antigen; immunostimulation; ctla-4; cancer control; cytotoxic t lymphocyte antigen 4; cell interaction; cd134 antigen; t lymphocyte activation; inducible nitric oxide synthase; mouse model; immune checkpoint blockade; leukocyte activation; ox40; ctla-4 antigen; nivolumab; human; male; female; article; neutrophil extracellular traps; antigenic heterogeneity; antitumorigenic activity; immune checkpoint protein; adoptive t cell therapies; anti-tumor neutrophils; tumor hetergeneity; antigenic escape; antigenic drift and shift |
| Journal Title: | Cell |
| Volume: | 186 |
| Issue: | 7 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2023-03-01 |
| Start Page: | 1432 |
| End Page: | 1447.e17 |
| Language: | English |
| DOI: | 10.1016/j.cell.2023.03.007 |
| PUBMED: | 37001503 |
| PROVIDER: | scopus |
| PMCID: | PMC10994488 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 May 2023 -- Source: Scopus |
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