Myeloma Induce Fapα+ Macrophage to Remodel Immune Microenvironment Which Lead to Anti-PD-1 Dilemma

Background: Multiple myeloma（MM） is a hematologic cancer which is characterized by clonal immune globulin. In recent years, FAPα+ fibroblast has been found in many tumor microenvironments, and play an important role in tumor immune escape. Furthermore, we find monocyte-derived macrophages can also express FAPα+ under existence of MM cell line.

Objective：Explore the impact of FAPα+ Macrophage in MM immune microenvironment.

Methods：Western blot(WB) and flow cytometry(FCM) was used to detect the expression of FAPα+ on macrophages. WB was used to detect the PDL1 altering. FCM was used to detect FAPα+ PDL1+macrophages in patient with myeloma. FCM was used to detect apoptosis of CD4+/CD8+ T cells and MM cells.

Results: 1.MM cell line can induce FAPα+ expression on Macrophage through TGFβ1 or CSF1. 2.Over-expression FAPα on macrophage can promote the expression of PDL1 and knock-down FAPα can reduce PDL1. 3.FAPα can increases mRNA PDL1 and partially inhibits ubiquitination mediating autophagy of PDL1. 4.Over-expression FAPα on macrophage can induce CD4+/CD8+T cell apoptosis and knock-down FAPα can reduce T cell apoptosis. 5. FAPα inhibitor combined with anti-PDL1 or anti-PD1 monoclonal antibody can promote CD138+MM cell apoptosis.

Conclusions: MM can induce macrophage expressing FAPα to further promote PDL1 expression and mediate MM immune escape. Combination of FAPα inhibitor with anti-PDL1 or anti-PD1 monoclonal antibody may facilitate immunotherapy effect in MM treatment.

Key words: FAPα, Macrophage, PDL1, T cell, Immunotherapy