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99 T cell immunotherapies trigger neutrophil activation to eliminate tumor antigen escape variants
  1. Daniel Hirschhorn1,
  2. Sadna Budhu1,
  3. David Schröder1,
  4. Lukas kraehenbuehl1,
  5. Anne-Laurent Flammar1,
  6. Andrew Chow1,
  7. Isabell Schulze1,
  8. Sara Schad1,
  9. Jacob Ricca1,
  10. Billel Gasmi1,
  11. Olivier De Henau1,
  12. Levi Mangarin1,
  13. David Redmond2,
  14. Czrina Cortez1,
  15. Cailian Liu1,
  16. Aliya Holland1,
  17. Mathieu Gigoux1,
  18. Asrhi Arora1,
  19. Katherine Panageas1,
  20. Gabrielle Rizzuto3,
  21. Jean Albrengues4,
  22. Mikala Egeblad4,
  23. Jedd Wolchok1 and
  24. Taha Merghoub1
  1. 1Memorial Sloan Kettering Cancer Center, New York, NY, USA
  2. 2Cornell Medical School, New York, USA
  3. 3University of California San Francisco, San Francisco, USA
  4. 4Cold Spring Harbor Laboratories, Cold Spring Harbor, NY, USA


Background Targeted immune-based therapies such as adoptive T cell transfer (ACT) are often ineffective because tumors evolve over time and under selective pressure display antigen loss variant clones. A classic example in melanoma is de-differentiation and loss of expression of antigenic proteins. Therapies that activate multiple branches of the immune system may eliminate such escape variants

Methods Here we show that melanoma-specific CD4+ ACT therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate large melanoma tumors with clonal escape variants.

Results Early on-target recognition of melanoma antigens by adoptively transferred tumor-specific CD4+ T cells was required. Surprisingly, however, complete tumor eradication was partially dependent on neutrophils. Supporting these findings, extensive neutrophil activation and neutrophil extracellular traps were found in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade.

Conclusions Our findings uncover a novel interplay between T cells mediating the initial tumor- and tissue-specific immune response, and neutrophils mediating tumor destruction of antigen loss variants.

Ethics Approval All tissues were collected at MSKCC following study protocol approval by the MSKCC Institutional Review Board. All mouse procedures were performed in accordance with institutional protocol guidelines at Memorial Sloan-Kettering Cancer Center (MSKCC) under an approved protocol.

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