Matrix proteoglycans in tumor inflammation and immunity

Abstract

Cancer immunoediting progresses through elimination, equilibrium, and escape. Each of these phases is characterized by breaching, remodeling, and rebuilding tissue planes and structural barriers that engage extracellular matrix (ECM) components, in particular matrix proteoglycans. Some of the signals emanating from matrix proteoglycan remodeling are readily co-opted by the growing tumor to sustain an environment of tumor-promoting and immune-suppressive inflammation. Yet other matrix-derived cues can be viewed as part of a homeostatic response by the host, aiming to eliminate the tumor and restore tissue integrity. These latter signals may be harnessed for therapeutic purposes to tip the polarity of the tumor immune milieu toward anticancer immunity. In this review, we attempt to showcase the importance and complexity of matrix proteoglycan signaling in both cancer-restraining and cancer-promoting inflammation. We propose that the era of matrix diagnostics and therapeutics for cancer is fast approaching the clinic.

Keywords: dendritic; immunotherapy; matrix; proteoglycans; versican.

Graphical abstract

Figure 1.

Matrix proteoglycans in cancer evolution and immunoediting. Cancers are “wounds that do not heal.” Immunoediting refers to the distinct stages of interfacing between the host immune system and the developing cancer. There are three stages: elimination, equilibrium, and escape (see text for details). Extracellular matrix remodeling regulates key signaling pathways at each step. The case is illustrated by versican (VCAN), a versatile large matrix proteoglycan that possesses diverse context-specific immunoregulatory or immunostimulatory roles, depending on its abundance, isoform structure, and proteolysis status (10). We propose the following model based on work by our group and others (–13): during elimination, robust VCAN proteolysis releases the immunostimulatory fragment (matrikine), versikine, that regulates stimulatory dendritic cells (conventional type 1 dendritic cells, cDC1) promoting immune destruction of the tumor through enhanced neoantigen recognition. In equilibrium, a precarious balance is established between immunostimulatory proteolyzed VCAN products and parental, nonproteolyzed immunoregulatory VCAN that allows the propagation of tumors with active, but progressively ineffectual, immune surveillance. In escape, progressive fibrosis and immunosuppression [e.g., through TGF-β (14)] attenuates VCAN proteolysis and results in the unbalanced immunoregulatory activity of nonproteolyzed VCAN. In these latter stages, immunosuppressive signals from receptors recognizing collagen may further promote immune exclusion (15, 16). Created with BioRender.com.

Figure 2.

Immunomodulatory roles of intracellular PG. Serglycin (SRGN) can modulate the activation status of the complement system. SRGN-CD44 interaction activates intracellular signaling pathways, such as NF-κB, promoting tumor aggressiveness. SRGN regulates IL-8 and TGF-β secretion, thus controlling crucial inflammatory networks in the TME. PG, proteoglycan. Created with BioRender.com.

Figure 3.

Immunomodulatory roles of transmembrane PG. Syndecan-1 (Sdc-1) regulates NF-κB and STAT-dependent inflammatory networks in tumor cells as well as TME immune cell polarization/activity through Notch. CSC, cancer stem cell; IBC, inflammatory breast cancer; PG, proteoglycan. Created with BioRender.com.

Figure 4.

Immunomodulatory roles of small leucine-rich PG (SLRPGs). Soluble biglycan and decorin bind TLR-2 and -4, resulting in production of various cytokines and chemokines, such as proinflammatory TNF-α and IL-1β, as well as anti-inflammatory IL-10. Decorin sequesters TGF-β and reduces the availability of miR-21, which results in decrease in IL-10 secretion. Biglycan can cluster TLR2/4 and purinergic receptors, P2X_4/P2X₇. APC, antigen-presenting cell; PG, proteoglycan. Created with BioRender.com.

Figure 5.

Immunomodulatory roles of large extracellular PG. Tumor- or stromal-derived versican (VCAN) leads to DC dysfunction through TLR-2 activation. Stromal nonproteolyzed VCAN also promotes exclusion of CD8⁺ T cells from TME. Versikine, an N-terminal bioactive fragment (matrikine), promotes CD8⁺ influx in the TME through regulation of cDC1 abundance and activation. The balance between nonproteolyzed VCAN and versikine appears to critically influence tumor immune infiltration density. DC, dendritic cell; PG, proteoglycan. Created with BioRender.com.