Targeting tumor-resident mast cells for effective anti-melanoma immune responses

Immune checkpoint blockade has revolutionized cancer treatment. Patients developing immune mediated adverse events, such as colitis, appear to particularly benefit from immune checkpoint inhibition. Yet, the contributing mechanisms are largely unknown. We identified a systemic LPS signature in melan...

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Bibliographic Details
Published in:	JCI insight Vol. 4; no. 19
Main Authors:	Kaesler, Susanne, Wölbing, Florian, Kempf, Wolfgang Eberhard, Skabytska, Yuliya, Köberle, Martin, Volz, Thomas, Sinnberg, Tobias, Amaral, Teresa, Möckel, Sigrid, Yazdi, Amir, Metzler, Gisela, Schaller, Martin, Hartmann, Karin, Weide, Benjamin, Garbe, Claus, Rammensee, Hans-Georg, Röcken, Martin, Biedermann, Tilo
Format:	Journal Article
Language:	English
Published:	American Society for Clinical Investigation 03-10-2019
Online Access:	Get full text
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Summary:	Immune checkpoint blockade has revolutionized cancer treatment. Patients developing immune mediated adverse events, such as colitis, appear to particularly benefit from immune checkpoint inhibition. Yet, the contributing mechanisms are largely unknown. We identified a systemic LPS signature in melanoma patients with colitis following anti–cytotoxic T lymphocyte–associated antigen 4 (anti–CTLA-4) checkpoint inhibitor treatment and hypothesized that intestinal microbiota–derived LPS contributes to therapeutic efficacy. Because activation of immune cells within the tumor microenvironment is considered most promising to effectively control cancer, we analyzed human and murine melanoma for known sentinels of LPS. We identified mast cells (MCs) accumulating in and around melanomas and showed that effective melanoma immune control was dependent on LPS-activated MCs recruiting tumor-infiltrating effector T cells by secretion of CXCL10. Importantly, CXCL10 was also upregulated in human melanomas with immune regression and in patients with colitis induced by anti–CTLA-4 antibody. Furthermore, we demonstrate that CXCL10 upregulation and an MC signature at the site of melanomas are biomarkers for better patient survival. These findings provide conclusive evidence for a “Trojan horse treatment strategy” in which the plasticity of cancer-resident immune cells, such as MCs, is used as a target to boost tumor immune defense. Targeted activation of melanoma-associated mast cells initiates effective tumor immune defense by CXCL10-induced recruitment of tumor-infiltrating T cells.
ISSN:	2379-3708 2379-3708
DOI:	10.1172/jci.insight.125057