A subpopulation of CD146^(+) macrophages enhances antitumor immunity by activating the NLRP3 inflammasome

As one of the main tumor-infiltrating immune cell types, tumor-associated macrophages (TAMs) determine the efficacy of immunotherapy. However, limited knowledge about their phenotypically and functionally heterogeneous nature restricts their application in tumor immunotherapy. In this study, we identified a subpopulation of CD146+ TAMs that exerted antitumor activity in both human samples and animal models. CD146 expression in TAMs was negatively controlled by STAT3 signaling. Reducing this population of TAMs promoted tumor development by facilitating myeloid-derived suppressor cell recruitment via activation of JNK signaling. Interestingly, CD146 was involved in the NLRP3 inflammasome-mediated activation of macrophages in the tumor microenvironment, partially by inhibiting transmembrane protein 176B (TMEM176B), an immunoregulatory cation channel. Treatment with a TMEM176B inhibitor enhanced the antitumor activity of CD146+ TAMs. These data reveal a crucial antitumor role of CD146+ TAMs and highlight the promising immunotherapeutic approach of inhibiting CD146 and TMEM176B.

Targeting the CD146/Galectin-9 axis protects the integrity of the blood-brain barrier in experimental cerebral malaria

Cerebral malaria(CM)is a life-threatening diffuse encephalopathy caused by Plasmodium falciparum,in which the destruction of the blood–brain barrier(BBB)is the main cause of death.However,increasing evidence has shown that antimalarial drugs,the current treatment for CM,do little to protect against CM-induced BBB damage.Therefore,a means to alleviate BBB dysfunction would be a promising adjuvant therapy for CM.The adhesion molecule CD146 has been reported to be expressed in both endothelial cells and proinflammatory immune cells and mediates neuroinflammation.Here,we demonstrate that CD146 expressed on BBB endothelial cells but not immune cells is a novel therapeutic target in a mouse model of experimental cerebral malaria(eCM).Endothelial CD146 is upregulated during eCM development and facilitates the sequestration of infected red blood cells(RBCs)and/or proinflammatory lymphocytes in CNS blood vessels,thereby promoting the disruption of BBB integrity.Mechanistic studies showed that the interaction of CD146 and Galectin-9 contributes to the aggregation of infected RBCs and lymphocytes.Deletion of endothelial CD146 or treatment with the anti-CD146 antibody AA98 prevents severe signs of eCM,such as limb paralysis,brain vascular leakage,and death.In addition,AA98 combined with the antiparasitic drug artemether improved the cognition and memory of mice with eCM.Taken together,our findings suggest that endothelial CD146 is a novel and promising target in combination with antiparasitic drugs for future CM therapies.