Potent CTLs can be induced against tumor cells in an environment of lower levels of systemic MFG‐E8

Abstract

AbstractThe direction and magnitude of immune responses are critically affected when dead cells are disposed of. Milk fat globule‐epidermal growth factor‐factor 8 (MFG‐E8) promotes the engulfment of apoptotic normal and cancerous cells without inducing inflammation. We have previously reported that a certain proportion of the cancer cells express abundant MFG‐E8, and that such expression is associated with the shorter survival of patients with esophageal cancer who had received chemotherapy before surgery. However, the influence of tumor‐derived and systemically existing MFG‐E8 on antitumor immune responses has not yet been fully investigated. Herein, we showed that CTL‐dependent antitumor immune responses were observed in mice with no or decreased levels of systemic MFG‐E8, and that such responses were enhanced further with the administration of anti‐PD‐1 antibody. In mice with decreased levels of systemic MFG‐E8, the dominance of regulatory T cells in tumor‐infiltrating lymphocytes was inverted to CD8+ T cell dominance. MFG‐E8 expression by tumor cells appears to affect antitumor immune responses only when the level of systemic MFG‐E8 is lower than the physiological status. We have also demonstrated in the clinical setting that lower levels of plasma MFG‐E8, but not MFG‐E8 expression in tumor cells, before the treatment was associated with objective responses to anti‐PD‐1 therapy in patients with non‐small cell lung cancer. These results suggest that systemic MFG‐E8 plays a critical role during the immunological initiation process of antigen‐presenting cells to increase tumor‐specific CTLs. Regulation of the systemic level of MFG‐E8 might induce efficient antitumor immune responses and enhance the potency of anti‐PD‐1 therapy.