Targeting myeloid suppressive cells revives cytotoxic anti-tumor responses in pancreatic cancer

• Published in: iScience Vol. 25; no. 11; p. 105317
• Main Authors: Sarhan, Dhifaf, Eisinger, Silke, He, Fei, Bergsland, Maria, Pelicano, Catarina, Driescher, Caroline, Westberg, Kajsa, Benitez, Itziar Ibarlucea, Hamoud, Rawan, Palano, Giorgia, Li, Shuijie, Carannante, Valentina, Muhr, Jonas, Önfelt, Björn, Schlisio, Susanne, Ravetch, Jeffrey V., Heuchel, Rainer, Löhr, Matthias J., Karlsson, Mikael C.I.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18-11-2022; Elsevier
• Subjects: Cancer; Components of the immune system; Immunology; Medicin och hälsovetenskap; Components of the immune system; Immunology; Cancer
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2022.105317

Immunotherapy for cancer that aims to promote T cell anti-tumor activity has changed current clinical practice, where some previously lethal cancers have now become treatable. However, clinical trials with low response rates have been disappointing for pancreatic ductal adenocarcinoma (PDAC). One suggested explanation is the accumulation of dominantly immunosuppressive tumor-associated macrophages and myeloid-derived suppressor cells in the tumor microenvironment (TME). Using retrospectively collected tumor specimens and transcriptomic data from PDAC, we demonstrate that expression of the scavenger receptor MARCO correlates with poor prognosis and a lymphocyte-excluding tumor phenotype. PDAC cell lines produce IL-10 and induce high expression of MARCO in myeloid cells, and this was further enhanced during hypoxic conditions. These myeloid cells suppressed effector T and natural killer (NK) cells and blocked NK cell tumor infiltration and tumor killing in a PDAC 3D-spheroid model. Anti-human MARCO (anti-hMARCO) antibody targeting triggered the repolarization of tumor-associated macrophages and activated the inflammasome machinery, resulting in IL-18 production. This in turn enhanced T cell and NK cell functions. The targeting of MARCO thus remodels the TME and represents a rational approach to make immunotherapy more efficient in PDAC patients.
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•Pancreatic tumors drive an immunosuppressive phenotype of myeloid cells•Antibodies activate MARCO-expressing myeloid cells to release cytotoxic cells•Expression of MARCO is connected to decreasing survival in human pancreatic cancer
Immunology; Components of the immune system; Cancer