Abstract
Expression of the transmembrane protein PD-L1 is frequently up-regulated in cancer. Since PD-L1-expressing cells can induce apoptosis or anergy of T lymphocytes through binding to PD1 receptor, the PD-L1-mediated inhibition of activated PD1+ T cells considered as a major pathway for tumor immune escape. However, the mechanisms that regulate the expression of PD-L1 in the tumor microenvironment not fully understood. Analysis of organotypic tumor tissue slice cultures, obtained from tumor-bearing mice as well as from cancer patients, revealed that tumor-associated hyaluronan (HA) supports the development of the immunosuppressive PD-L1+ macrophages. Using genetically modified tumor cells, we identified both epithelial tumor cells and cancer-associated fibroblasts (CAFs) as the major source of HA in the tumor microenvironment. HA-producing tumor cells and, in particular CAFs of bone marrow origin, directly interact with tumor-recruited Hyal2+ myeloid cells forming the large stromal congregates/clusters that are highly enriched for both HA and PD-L1. Furthermore, similar cell clusters comprising of HA-producing fibroblasts and PD-L1+ macrophages were detected in the tumor-draining lymph nodes. Collectively, our findings indicate that the formation of multiple large HA-enriched stromal clusters that support the development of PD-L1-expressing antigen-presenting cells in the tumor microenvironment and draining lymph nodes could contribute to the immune escape and resistance to immunotherapy in cancer.
Competing Interest Statement
The authors have declared no competing interest.