The Role And Mechanism Of MC5R In Tumor-induced Myelopoiesis And Immunosuppression

Tumor-induced immune supression is a major barrier to immunotherapy.A growing body of researches suggest that tumor can enhance myelopoiesis and induce myeloid cells such as tumor-associated macrophages(TAMs)and Myeloid derived suppressor cells(MDSCs).These myeloid cells could inhibit antitumor immunity,thus promoting tumor progression.Therefore,it’s known the mechanism of tumor-induced myelopoiesis not only helps to reveal the formation mechanism of tumor immunosuppression,but also provides new targets and strategies for immunotherapy.The melanocortin receptors(MCRs)are G-protein-coupled receptors and belong to the GPCRs family,which are made up of five members at the moment.They are named MC1R-MC5R.The last MCR to be discovered was MC5R.However,it’s unknown about its role in physiologic and pathologic conditions.The aim of this study is to investigate the role and mechanism of MC5R in tumor-induced myelopoiesis and immunosuppression.The results are as follows:1.MC5R inhibits antitumor immunity and promotes tumors growth.We fulfilled tumor-bearing experiments in Mc5r-/-mice,including subcutaneous and metastatic tumour models.While comparing with control mice,we found tumor growth rate was retarded in Mc5r-/-mice and survival was also prolonged.In addition,the numer of tumor infiltrating CD4+T,CD8+T and NK cells is significantly increased and the level of IFN-y is heightened.These results indicate MC5R inhibits the function of antitumor immune cells and promotes the development of tumors.2.MC5R promotes myelopoiesis and inhibits antitumor immunity.We performed tumor-bearing experiments in Mc5r-/-mice.While comparing with control mice,we found the number of myeloid cells(PMN-MDSCs/MMDSCs/TAMs/DCs)in tumor,spleen and blood was reduced and the expansion of myeloid progenitor cells(LSKs/CMPs/GMPs/MDPs)was also abrogated in Mc5r-/mice.The results indicate MC5R can promote tumor-induced myelopoiesis.3.Hematopoietic progenitor Mc5r deficiency enhances antitumor immunity.We found that MC5R was highly expressed on hematopoietic progenitor cells LSKs(Lin-Sca1+c-Kit+).To study the role of hematopoietic progenitor MC5R in tumor immunity,we generated Mc5fl/fl Vavcre mice(Mc5r gene is ablated in hematopoietic progenitor cells)and performed tumor-bearing experiments.While comparing with control mice,we found the tumor growth rate was slowed down in Mc5rfl/fl Vavcre mice.In addition,the numer of tumor infiltrating cells was significantly increased and the antitumor ability was significantly improved.Meanwhile,the number of myeliod cells in tumor、spleen and blood was reduced and the number of bone marrow precursor cells was also suppressed.These results indicate that hematopoietic progenitor MC5R inhibits antitumor immunity and accelerates the development of tumors.4.α-MSH-MC5R promotes myelopoiesis though ERK-STAT3 pathway.We then studied the mechanism of how MC5R regulates myelopoiesis.Further analysis showed that MC5R’s endogenous ligand α-melanocyte stimulating hormone(α-MSH)can promote the proliferation of myeloid precursor LSKs via ERK-STAT3 pathway.5.Antagonizing MC5R promotes antitumor immunity and anti-PD-1 immunotherapy.We next investigated the possibility of targeting MC5R in cancer therapy.We used reported cyclic peptide MC5R antagonist that specifically blocks MC5R to perform tumor therapy in mice.The antagonist treatments significantly delayed the growth of Lung cancer,Fibrosarcoma and Melanoma,and enhanced antitumor immunity.In addition,antagonizing MC5R can inhibit the generation of myeloid cells and the expansion of bone marrow precursor cells.Finally,in order to confirm whether blocking MC5R can improve the response rate of ICB therapy,we conducted a combined treatment experiment on PD-1-sensitive MCA205 tumor model and resistant LLC and B16F10-GMCSF tumor model.It was found that the combination of Antagonist and anti-PD-1 antibody could effectively inhibit tumor growth and improve the survival of mice.6.MC5R is expressed on HSCs from PBMCs.At last,we investigated the clinical relevance of this study.We found that MC5R was highly expressed on hematopoietic stem cells(HSCs)from human peripheral blood mononuclear cells(PBMCs).In conclusion,our results suggest that MC5R and its antagonists have a potential application in tumor therapy and reversal of ICB resistance.MC5R may be a new immunotherapy target.