An immunosuppressive tumor population drives immunotherapy resistance of heterogeneous tumors

Abstract Intratumoral heterogeneity (ITH) – cellular and molecular diversity within a tumor is linked to failure of immunotherapy in multiple cancer types. A high degree ITH associated with poor infiltration T cells into the resistance immune checkpoint blockade (ICB) therapy. To determine how distinct populations heterogeneous tumors shape microenvironment this impacts therapy response, we modeled composed an RFP-tagged immunosuppressive population YFP-tagged pro-inflammatory population. The resulting contained patchwork regions YFP +cells, RFP or mixture +and +cells. Analysis infiltrates each region revealed higher frequency total CD4 cells, Th1 IFNg +CD8 compared regions, whereas macrophages exhibited opposite pattern. PD-1 CD40 agonist combinatorial antibody induced increase abundance but treatment did not clear tumors. Together, these results reveal that regional pattens are driven by local present region, treatment-induced global improvement alone sufficient induce clearance. Moreover, identified Cx3cl1 as driver dominant microenvironment, marked CD206 +macrophages decrease anti-tumoral neutrophils monocytes. These suggest drives new therapeutic target. Supported grants from Parker Institute for Cancer Immunotherapy (Project Grant)