T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants

Daniel Hirschhorn, Sadna Budhu, Lukas Kraehenbuehl, Mathieu Gigoux, David Schröder, Andrew Chow, Jacob M. Ricca, Billel Gasmi, Olivier De Henau, Levi Mark B. Mangarin, Yanyun Li, Linda Hamadene, Anne Laure Flamar, Hyejin Choi, Czrina A. Cortez, Cailian Liu, Aliya Holland, Sara Schad, Isabell Schulze, Allison Betof WarnerTravis J. Hollmann, Arshi Arora, Katherine S. Panageas, Gabrielle A. Rizzuto, Rebekka Duhen, Andrew D. Weinberg, Christine N. Spencer, David Ng, Xue Yan He, Jean Albrengues, David Redmond, Mikala Egeblad, Jedd D. Wolchok, Taha Merghoub

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1432-1447.e17
Issue number7
StatePublished - Mar 30 2023
Externally publishedYes


  • CTLA-4
  • OX40
  • adoptive T cell therapies
  • anti-tumor neutrophils
  • antigenic heterogeneity
  • immune checkpoint blockade
  • immunotherapy
  • neutrophil extracellular traps
  • neutrophils
  • tumor hetergeneity

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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