Hartman Institute for Therapeutic Organ Regeneration

T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants.

TitleT cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants.
Publication TypeJournal Article
Year of Publication2023
AuthorsHirschhorn D, Budhu S, Kraehenbuehl L, Gigoux M, Schröder D, Chow A, Ricca JM, Gasmi B, De Henau O, Mangarin LMark B, Li Y, Hamadene L, Flamar A-L, Choi H, Cortez CA, Liu C, Holland A, Schad S, Schulze I, Warner ABetof, Hollmann TJ, Arora A, Panageas KS, Rizzuto GA, Duhen R, Weinberg AD, Spencer CN, Ng D, He X-Y, Albrengues J, Redmond D, Egeblad M, Wolchok JD, Merghoub T
JournalCell
Volume186
Issue7
Pagination1432-1447.e17
Date Published2023 Mar 30
ISSN1097-4172
KeywordsAnimals, Antigenic Drift and Shift, CTLA-4 Antigen, Immunotherapy, Melanoma, Mice, Neutrophils, T-Lymphocytes
Abstract

<p>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.</p>

DOI10.1016/j.cell.2023.03.007
Alternate JournalCell
PubMed ID37001503
PubMed Central IDPMC10994488
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R01 CA237413 / CA / NCI NIH HHS / United States
P30 CA045508 / CA / NCI NIH HHS / United States
R01 CA056821 / CA / NCI NIH HHS / United States
P50 CA211024 / CA / NCI NIH HHS / United States

Weill Cornell Medicine
Hartman Institute for Therapeutic Organ Regeneration
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