Deregulated hyaluronan metabolism in the tumor microenvironment drives cancer inflammation and tumor-associated immune suppression

Abstract

Hyaluronan (HA) is known to be a prominent component of the extracellular matrix in tumors, and many solid cancers are characterized by aberrant HA metabolism resulting in increased production in tumor tissue. HA has been implicated in regulating a variety of cellular functions in tumor cells and tumor-associated stromal cells, suggesting that altered HA metabolism can influence tumor growth and malignancy at multiple levels. Importantly, increased HA production in cancer is associated with enhanced HA degradation due to high levels of expression and activity of hyaluronidases (Hyal). Understanding the complex molecular and cellular mechanisms involved in abnormal HA metabolism and catabolism in solid cancers could have important implications for the design of future cancer therapeutic approaches. It appears that extensive crosstalk between immune cells and HA-enriched stroma contributes to tumor growth and progression in several ways. Specifically, the interaction of tumor-recruited Hyal2-expressing myeloid-derived suppressor cells (MDSCs) of bone marrow origin with HA-producing cancer-associated fibroblasts and epithelial tumor cells results in enhanced HA degradation and accumulation of small pro-inflammatory HA fragments, which further drives cancer-related inflammation. In addition, hyaluronan-enriched stroma supports the transition of tumor-recruited Hyal2⁺MDSCs to the PD-L1⁺ tumor-associated macrophages leading to the formation of an immunosuppressive and tolerogenic tumor microenvironment. In this review, we aim to discuss the contribution of tumor-associated HA to cancer inflammation, angiogenesis, and tumor-associated immune suppression. We also highlight the recent findings related to the enhanced HA degradation in the tumor microenvironment.

Keywords: HYAL2; MDSC; PD-L1; cancer inflammation; hyaluronan degradation; tumor microenvironment; tumor-associated immune suppression; tumor-associated macrophages.

Figure 1

Increased degradation of extracellular hyaluronan in tumor tissue. Normal non-malignant bladder tissue produce HA with mostly high molecular weight (A). In contrast, the tumor bladder tissue is characterized by enhanced HA degradation and accumulation of tumor-associated HA with low molecular weight (B).

Figure 2

Hyal2 translocation is required for the degradation of extracellular hyaluronan. In a quiescent state, the Hyal2 molecule in myeloid cells resides predominantly in intracellular space (A). However, activation of the CD44 signaling pathway results in translocation of Hyal2 to the cellular membrane, enabling the degradation of extracellular HA (B). Depicted yellow crosses indicate the activated status of the enzyme Hyal2.

Figure 3

Tumor-recruited Hyal2⁺ MDSCs directly contribute to the development of the immunosuppressive tumor microenvironment by forming PD-L1⁺ macrophage clusters in the hyaluronan-enriched stroma. Tumors constantly secrete significant amounts of chemokines that attract the Hyal2⁺ MDSCs from bone marrow. Once recruited to the tumor, Hyal2-expressing myeloid cells start degradation of extracellular HA in the tumor microenvironment. Direct interaction of tumor-recruited myeloid cells with HA-producing cancer-associated fibroblasts (CAFs) and epithelial tumor cells leads to the accumulation of small HA pro-inflammatory and pro-angiogenic fragments. Hyal2⁺ MDSCs differentiate into immunosuppressive tumor-associated PD-L1⁺ macrophages (PD-L1⁺ TAMs), forming large PD-L1-expressing cell clusters in HA-enriched tumor stroma.

Figure 4

Tumor-associated hyaluronan directly supports the development of immunosuppressive PD-L1⁺ macrophages in the tumor microenvironment. Freshly prepared tumor tissue slices were cultured for twenty-four hours. Then cultures were fixed with 4% formaldehyde and stained PD-L1 (red) and HA (green). Representative IF image is shown.