Previous studies have provided evidence for both pro-tumor and anti-tumor neutrophil activity. Neutrophils have been associated with cancer cell proliferation, metastasis and angiogenesis, and neutrophil activity has been shown to protect tumors from T cell responses. However, neutrophils have also been shown to kill tumor cells and promote anti-tumor immunity. Importantly, our understanding of how neutrophils affect immunotherapy remains incomplete. Now, two studies published in Cell show the importance of neutrophils for tumor control in the context of immunotherapy.
Hirschhorn et al. report that neutrophils are essential for the elimination of cancer variants that escape immune recognition. The authors first co-implanted B16 melanomas (TRP1+) and B78H1 melanomas (TRP1−) in mice, which were preconditioned with cyclophosphamide (CTX) followed by treatment with adoptive transfer of TRP1 T cells and an anti-OX40 antibody. Treatment eliminated B16 but not B78H1 tumors; however, heterogenous B16–B78H1 tumors were eliminated, despite not all cancer cells expressing the target antigen TRP1. Hematoxylin-and-eosin staining, in combination with flow cytometry and immunofluorescence, confirmed the presence of neutrophils in the tumors of treated mice. The authors then exposed naive neutrophils to tumor extracts from treated mice. After exposure, the neutrophils displayed increased killing of B78H1 cells, which suggests that TRP1 T cells can reprogram neutrophils to eliminate antigen-loss variants. Finally, mice with heterogeneous B16–B78H1 tumors that underwent the same treatment of CTX followed by TRP1 T cells and anti-OX40 antibody were depleted of neutrophils. Tumor growth and mouse death were observed in almost all neutrophil-depleted mice, but not in control mice depleted of monocytes, macrophages or natural killer cells, which suggests a fundamental role for neutrophils in eliminating antigen-escape variants.
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