Peritoneal resident macrophages constitute an immunosuppressive environment in peritoneal metastasized colorectal cancer
J Saris, Andrew Y. F. Li Yim, S. Bootsma, Kristiaan Lenos, Rosalia Franco Fernandez, HA Khan, Jan Verhoeff, Dennis Poel, N M Mrzlikar, Liming Xiong, Marlies P. Schijven, Nicole C.T. van Grieken, Onno Kranenburg, Manon E. Wildenberg, Adrian Logiantara, Chiara Jongerius, Juan J. García‐Vallejo, Suzanne S. Gisbertz, Sarah Derks, Jurriaan B. Tuynman, Geert D’Haens, Louis Vermeulen, Joep Grootjans
Abstract
Patients with peritoneal metastasized colorectal cancer (PM-CRC) have a dismal prognosis. We hypothesized that an immunosuppressive environment in the peritoneal cavity underlies poor prognosis. We define the composition of the human peritoneal immune system (PerIS) using single-cell technologies in 18 patients with- and without PM-CRC, as well as in matched peritoneal metastases (n = 8). Here we show that the PerIS contains abundant immunosuppressive C1Q+VSIG4+ and SPP1+VSIG4+ peritoneal-resident macrophages (PRMs), as well as monocyte-like cavity macrophages (mono-CMs), which share features with tumor-associated macrophages, even in homeostasis. In PM-CRC, expression of immunosuppressive cytokines IL10 and VEGF increases, while simultaneously expression of antigen-presenting molecules decreases in PRMs. These intratumoral suppressive PRMs originate from the PerIS, and intraperitoneal depletion of PRMs in vivo using anti-CSF1R combined with anti-PD1 significantly reduces tumor burden and improves survival. Thus, PRMs define a metastatic site-specific immunosuppressive niche, and targeting PRMs is a promising treatment strategy for PM-CRC. Presence of peritoneal metastasis is associated with a decreased survival in patients with colorectal cancer. Here, the authors show that peritoneal-resident macrophages promote the formation of an immunosuppressive environment that facilitate peritoneal metastasis in colorectal cancer.