Cutaneous diffuse large B-cell lymphoma induces a macrophage immunosuppressive phenotype through IL-10 secretion

Overview & Synopsis

Points• PCDLBCL-LT polarizes macrophages toward an immunosuppressive phenotype and function through a pivotal IL-10 secretion.• Macrophages promote tumor B-cell growth and protect them against doxorubicininduced cell death in vitro.Primary cutaneous diffuse large B-cell lymphoma (PCDLBCL), leg type (PCDLBCL-LT) is a rare subset of DLBCL that exhibits genetic features shared with LBCL of immuneprivileged sites (notably the MYD88 L265P mutation) and is enriched in tumor-associated macrophages expressing M2 markers. Using a unique PCDLBCL-LT cell line (ARSI cell line) developed in our institute, we sought to mechanistically decipher the interplay between lymphoma cells and macrophages. We demonstrate that ARSI cells induce phenotypic, transcriptional, and functional changes in macrophages obtained from primary monocytes and THP-1 cell line. These changes do not require cell-cell contact, and proteome analysis of ARSI secretome reveals high concentration of several cytokines and chemokines known to affect macrophages, including interleukin-10 (IL-10). We then demonstrate that IL-10/ Interleukin 10 receptor subunit alpha (IL-10RA) interaction blockade inhibits macrophage polarization induced by tumor cells. These findings are reproduced when macrophages are cocultured with PCDLBCL-LT cells from different patient-derived xenografts. However, among 4 other DLBCL cell lines, only the MYD88-mutated OCI-Ly3 cell line exhibits similar effects, which highlights the variability of macrophage interplays and led us to hypothesize that macrophage shaping, beyond the cutaneous localization, may rely on specific genetics of tumor cells. Finally, we reveal that macrophages enhance tumor cell proliferation and promote resistance to doxorubicin in coculture. In conclusion, these results confirm the robustness of this model to study lymphoma cell and macrophage interplays, underline the critical role of IL-10 in lymphoma microenvironment modeling, and may contribute to better defining its specificities in an era of rising microenvironment-targeted therapies.