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Abstract 3842: Versican proteolysis is a predictive biomarker of tumor infiltrating lymphocytes within primary and metastatic colorectal cancer tumors


 Background: A major roadblock to immune-therapy response in many solid malignancies is the lack of tumor-infiltrating lymphocytes (TILs) found within their immune micro-environments. These immunologically cold tumors have lower response rates to immune-based therapies and among all colorectal cancers (CRC), only about six percent of patients have an objective response to immune checkpoint blockade (ICB). Versican (VCAN) accumulation has been found to be negatively correlated with TILs and its proteolysis into versikine (Vkine) correlates with higher TILs. In this study we analyze the association between VCAN accumulation/proteolysis and TILs in CRC from patients with both resectable primary CRCs and matched liver metastases.
 Methods: VCAN, Vkine, and TIL abundance were assessed via immunohistochemistry, with VCAN and Vkine being measured using an intensity binning system ranging from 0-3+ and TILs counted at 40X magnification for each tumor. Tumors were then designated as high (2 or 3+) or low (0 or 1) for both VCAN and Vkine. Tumors that were designated VCAN low and Vkine high are considered VCAN proteolytic predominant (VPP) and all other combinations are considered VCAN proteolytic weak (VPW).
 Results: 53% of both primary and metastatic tumors were designated VCAN low and 47% VCAN high. 59% of metastases from patients with VCAN-high primary tumors were also designated VCAN high, whereas 43% of metastases from patients with VCAN low primary tumors were designated VCAN high. When assessing proteolysis, it was found that 37% of primary tumors were designated VPP but only 26% of metastases were found to be VPP. When comparing proteolysis in a pairwise fashion, it was found that only 37% of VPP primaries had a VPP metastasis. An inverse correlation was again found between VCAN accumulation and TILs within primary CRCs. Tumors containing high levels of VCAN had an average of three TILs/high powered field (HPF), whereas tumors with low levels of VCAN had an average of 16 TILs/HPF (p=0.007). VPW tumors had an average of three TILs/HPF and VPP cores had an average of 21 TILs/HPF (p=0.009). VPW metastatic tumors had an average of eight TILs/HPF, whereas those that were VPP had an average of 15 TILs/HPF (p=0.01).
 Conclusion: Overall, these data confirm the inverse correlations between VCAN accumulation and TILs in primary CRCs. Additionally, VCAN proteolysis correlates with TILs in primary tumors and metastases. The potential for different VCAN accumulation/proteolysis in the primary tumor and metastatic disease will be an important consideration when studying VCAN further as a potential biomarker of immunotherapy response.
 Citation Format: Sean G. Kraus, Kristina A. Matkowskyj, Philip B. Emmerich, Wei Zhang, Linda Clipson, Cheri A. Pasch, Dustin A. Deming. Versican proteolysis is a predictive biomarker of tumor infiltrating lymphocytes within primary and metastatic colorectal cancer tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3842.