The inhibitory receptor CD300a functions as an immune checkpoint in a mouse model of breast cancer

Abstract Breast cancer (BC) is the second most common cancer type in women and still a major cause of death. In the USA it is estimated that 42,250 women will die in 2024 from BC. Over the last decade immunotherapy, especially blocking of immune checkpoints by monoclonal antibodies (mAbs), has entered the clinic in many cancer types, including BC. Still, intensive research is being carried out to increase the use of the approved drugs and to find new targets and new drugs. CD300a is an inhibitory receptor expressed in many immune cells. Its ligands, phosphatidylserine (PS) and phosphatidylethanolamine (PE), are expressed on activated and apoptotic immune cells as well as on several cancer cells. We hypothesized that PS and PE expressed on cancer cells might activate immune cell suppression via CD300a. Mast cells, the innate immune cells known mostly for their key function in allergic inflammation, express CD300a and were shown to have major regulatory roles in many cancer types, particularly in BC. To test the suggested role of CD300a in BC, we induced the mouse 4T1 BC model in WT and CD300a-KO mice. Smaller tumors were detected in the CD300a-KO mice together with a significant increase in MCs activation level. Culturing 4T1 cells together with WT mouse bone marrow derived MCs (BMMCs) reduced 4T1 cell number which was further reduced in co-culture with CD300a-KO-BMMCs. Finally, we found the immune-modulatory cytokine IL-10 in the supernatants of WT BMMCs but not in their CD300a-KO counterparts. Our results would imply that in BC, tumor cells activate CD300a expressed on MCs and probably on other immune cells to inhibit anti-tumorigenic immunity, therefore suggesting CD300a as an immunecheckpoint in BC.