Abstract 3282: Versican abundance/proteolysis as a biomarker for immunotherapy efficacy in intestinal cancers

Abstract Background: The composition of the tumor microenvironment (TME) can regulate T cell infiltration and potentially immunotherapy efficacy. Versican (VCAN), an extracellular matrix proteoglycan, regulates the presence of tumor infiltrating lymphocytes (TILs) and their activation, while its proteolytic byproduct, versikine (Vkine), can stimulate an immune response. Here we aim to validate our prior findings that VCAN status correlates with CD8+ T cell infiltration in intestinal cancers and evaluate the predictive role of VCAN/Vkine for patients undergoing immunotherapy for microsatellite instability high (MSI-H) cancers. Methods: A total of 28 consented subjects were identified with intestinal cancers that were MSI-H, high tumor mutation burden, or with alterations in mismatch repair genes as part of an IRB-approved protocol. Baseline characteristics, immunotherapy response, and survival data were collected. Cancer samples were obtained and stained for VCAN, Vkine, and CD8+ TILs. An intensity binning system was used to score VCAN and Vkine, ranging from 0-3. TILs were averaged across high power fields (HPF). Cancers with high VCAN (2-3) and any Vkine were categorized as VCAN proteolytic weak (VPW), cancers with low VCAN (0-1) and high Vkine (2-3) as VCAN proteolytic predominant (VPP), and cancers with both low VCAN (0-1) and low Vkine (0-1) as VCAN/Vkine low (VVL). Results: Clinical characteristics of the 28 subjects studied: median age 62.5 years (32-90); 17 females; 19 colon cancers; six rectal cancers; one rectosigmoid cancer and two small intestinal cancers. Further, nineteen were stage 3, nine were stage 4 and 71% were MSI-H. Six were VVL, one was VPP and 21 were VPW. The VVL and VPP cancers had a median of 27 CD8+ TILs/HPF, while the VPW cohort had a median of 15.7 (p=0015). CD8+ TILs in the MSI-H VPW subset trended higher than the microsatellite stable VPW cancers (21.7 versus 8.5; p=0.35). Thirteen subjects with MSI-H cancers received immunotherapy (10 pembrolizumab (PEMBRO), three ipilimumab (IPI) and nivolumab (NIVO)). Of these cancers, six were VPW and completed PEMBRO. None of the VPW cancers achieved a complete response to PEMBRO alone with most developing progressive disease. An additional VPW subject is still receiving therapy with a partial response to PEMBRO to date. Two patients with VPW cancers received IPI and NIVO and had complete responses. The four subjects with VVL or VPP cancers have all achieved a complete response and are alive without cancer recurrence. Three were treated with PEMBRO and one with IPI and NIVO. Conclusion: The VCAN status in the TME of intestinal cancers shows promise as a biomarker for T cell infiltration and response to immune checkpoint blockade. The ability of VCAN status to identify patients who are more likely to benefit from dual immune checkpoint blockade deserves further investigation. Citation Format: Elizabeth L. Field, Sean Kraus, Madeleine Buratti, Heidi Koehnke, Cheri A. Pasch, Fotis Asimakopoulos, Dustin A. Deming. Versican abundance/proteolysis as a biomarker for immunotherapy efficacy in intestinal cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3282.