PDL1-expressing macrophages infiltrate diffuse large B-cell lymphoma and promote lymphoma growth in a MYC-driven experimental model

The infiltration of diffuse large- and other mature B-cell lymphomas with T- and myeloid cells is a key tumor microenvironmental feature but is not currently factored into treatment decisions. Here, we have used multiplex immunofluorescence microscopy to quantify the immune infiltrates of >260 diffuse large B-cell- (DLBCL), follicular- (FL) and mantle cell lymphomas (MCL), and chronic lymphocytic leukemias (CLL) relative to clinical outcomes, mutational landscape and phenotype. MCL were found to be the "coldest" and DLBCL the "hottest" entities. The lymphoma microenvironment of DLBCL featured numerically dominant populations of CD8⁺ and T-follicular helper (Tfh) T-cells that were indicative of superior prognosis. Mutations in EZH2, PTEN and KMT2D were overrepresented in DLBCL with low CD8⁺ T-cell infiltration. A unique feature of DLBCL was its infiltration by large numbers of PDL1⁺ macrophages that constituted up to 70% of total cellularity. PDL1⁺ macrophage infiltration was mutually exclusive with regulatory T-cell infiltration. The inducible ablation of PDL1 on macrophages was sufficient to improve immune control of MYC-expressing lymphoma in a syngeneic immunocompetent model. These results implicate the macrophage/CD8⁺ T-cell axis as a key pathogenetic determinant and immunotherapeutic target in a subset of DLBCL patients with poor prognosis.