软骨寡聚基质蛋白、癌症相关成纤维细胞表型及多功能蛋白聚糖蛋白水解调控结直肠癌中CD8+ T细胞浸润

Background: Cytotoxic T cell infiltration in colorectal cancers (CRCs) is critical for immunotherapy response and is regulated by various tumor microenvironment (TME) factors. Cartilage oligomeric matrix protein (COMP), a large pentameric glycoprotein involved in extracellular matrix (ECM) organization and stability, has been implicated in elevated fibrosis and immunomodulation in CRC. Likewise, myofibroblastic and inflammatory cancer-associated fibroblasts (myCAFs and iCAFs) regulate ECM remodeling and immunomodulation in the TME. Versican (VCAN) and its proteolysis product, versikine (Vkine) also impact CD8+ T cell infiltration. Here, we evaluate the impact of COMP on CD8+ Tumor-infiltrating lymphocyte (TIL) abundance alone and in combination with CAF phenotypes and VCAN proteolysis status. Methods: Immunohistochemistry was performed on CRC samples from 243 patients to evaluate COMP, myCAF, alphaSMA, TAGLN, PDPN, ICAM1, CD8, VCAN, and Vkine. CD8+ TILs were quantified per high-power field (HPF). COMP was scored from 0-3 based on staining abundance and intensity in the cancer epithelium, CAFs, immune cells, ECM, and the total stromal compartment. All other stains were scored from 0-3 based on stromal abundance and intensity. alphaSMA and TAGLN scores were averaged to calculate a myCAF score, and PDPN and ICAM1 were averaged to calculate an iCAF score. CAF and VCAN status was assigned as per previous. Results: Abundant COMP was observed in the cancer epithelium (80%), CAFs (77%), immune cells (76%), ECM (36.2%), and stroma overall (64%). High stromal COMP expression is more prevalent in myCAF high cancers (25%) relative to iCAF high (8%) cancers. High stromal COMP expression is more prevalent in VCAN proteolytic weak (VPW, percent of samples 41%) vs VCAN/Vkine low (VVL, 15%) and VCAN proteolytic predominant (VPP, 19%) cancers. CD8+ TIL abundance increased with COMP expression across all compartments. A trend of higher CD8+ TIL abundance in stromal COMP high cancers relative to stromal COMP low cancers for iCAF high was observed (mean CD8+ TILs/HPF in COMP low cancers 8, COMP high cancers 10), while myCAF high cancers were comparable (5, 5). Interestingly, CD8+ TIL abundance was significantly higher in iCAF high cancers with high CAF COMP expression vs low CAF COMP (high CAF COMP mean CD8+ TILs/HPF 12, low CAF COMP 3, p=0.0488), though myCAF high cancers exhibit the opposite trend. CD8+ TIL abundance was also higher in stromal COMP high VPP cancers and VVL cancers vs VPW cancers (mean CD8+ TILs/HPF 19, 8 vs 4, respectively, p=1.398e-05). Conclusion: COMP is abundant in the CRC TME and can vary with other TME features. The presence of COMP correlates with enhanced CD8+ T cell infiltration in the setting of a pro-inflammatory TME, including VPP and iCAF high cancers. Mechanistic studies are needed to evaluate how COMP may enhance T cell infiltration.