Abstract 4052: Neutrophil recruitment and activation promotes cutaneous adverse effects with T cell immunotherapies

Abstract Immune-based therapies that induce tumor regression are often accompanied by immune-related adverse events (irAEs) which can occasionally present with severe and lethal symptoms. Currently, there are no well-defined preventative approaches to uncouple anti-tumor immunity from irAEs. Currently approved immunotherapies include agents that activate T cell responses, such as antibodies blocking immune checkpoints and infusion of tumor-derived, T cell receptor-transgenic or chimeric antigen receptor-modified T cells. While the beneficial and toxic effects of T cell-based therapies in the clinic are being extensively explored, the precise mechanisms underlying their activity remain the subject of investigation. In this study, we treated preclinical models of established melanomas with tumor-specific adoptive CD4+ T cell transfer in combination with T cell co-stimulation via OX40 agonism or CTLA-4 blockade. We found that, despite adequate T cell stimulation, acute local inflammation plays an important role in tumor elimination and the manifestation of irAEs. While stimulated T cells are necessary for initiating a therapeutic response, activation of endogenous neutrophils constitutes an important and necessary effector mechanism for both tumor destruction and the development of irAEs. Extensive neutrophil extracellular traps (NETs) were associated with irAEs. Furthermore, melanoma patients treated with immune checkpoint blockade with skin rashes equivalent to irAEs found in mice showed increased survival and NETs in biopsies from both rashes and tumors. Our results bring forward a novel paradigm where T cells prime an anti-tumor immune response that is followed by an inflammatory effector mechanism provided by the innate immune system, resulting in both curative and undesirable side effects in mice and patients. Citation Format: Daniel Hirschhorn, Lukas Kraehenbuehl, Sadna Budhu, Valeria Estrada Navarro, Levi Mark B Mangarin, Yacine Marouf, Jacob Ricca, Billel Gasmi, Olivier De Henau, Yanyun Li, Czrina Cortez, Hamadene Linda, Isabell Schulze, Cailian Liu, Katherine Panageas, Mario Lacuoture, Gabrielle A. Rizzuto, Mikala Egeblad, Jedd D. Wolchok, Taha Merghoub Merghoub. Neutrophil recruitment and activation promotes cutaneous adverse effects with T cell immunotherapies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4052.