TY - JOUR
T1 - Targeting tumor-resident mast cells for effective anti-melanoma immune responses
AU - Kaesler, Susanne
AU - Wölbing, Florian
AU - Kempf, Wolfgang Eberhard
AU - Skabytska, Yuliya
AU - Köberle, Martin
AU - Volz, Thomas
AU - Sinnberg, Tobias
AU - Amaral, Teresa
AU - Möckel, Sigrid
AU - Yazdi, Amir
AU - Metzler, Gisela
AU - Schaller, Martin
AU - Hartmann, Karin
AU - Weide, Benjamin
AU - Garbe, Claus
AU - Rammensee, Hans Georg
AU - Röcken, Martin
AU - Biedermann, Tilo
N1 - Publisher Copyright:
Copyright: © 2019, American Society for Clinical Investigation.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85072984168&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.125057
DO - 10.1172/jci.insight.125057
M3 - Article
C2 - 31578309
AN - SCOPUS:85072984168
SN - 2379-3708
VL - 4
JO - JCI Insight
JF - JCI Insight
IS - 19
M1 - e125057
ER -