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Abstract B12: Potential neoantigen release and increased lymphocyte activity is facilitated by matrix metalloproteinase-dependent cleavage of mutant matrisome peptides in cutaneous melanoma


 Introduction: Proteases in the cancer microenvironment have been studied for decades, with a general conclusion that such proteases facilitate the spread of cancer, although there is some controversy regrading that conclusion in later stages of cancer development. More recently, a very large collection of data regarding mutant amino acids in the potential substrates of the cancer microenvironment has become available.
 Methods: To better understand the potential impact of these mutant amino acids on protease function and cancer progression, we established a bioinformatics approach to assessing the impact of melanoma mutants, among a previously defined set of ECM structural proteins, on MMP2, a protease extensively associated with melanoma in terms of both protease sensitivity and MHC class I binding using original software. Additionally, T-cell receptor TRα and TRβ recombinations were bioinformatically obtained using whole-exome sequencing data from 479 melanoma tumor samples.
 Results: Tumor samples with mutant amino acids adjacent to ECM structural protein, MMP2-cleavage sites represented a better survival rate and a larger proportion of mutant peptides with high HLA class I binding affinities, particularly in comparison to melanoma samples lacking a T-cell infiltrate. Furthermore, even better MHC class I binders, as a group, were identified among the sample representing ECM structural proteins mutants not adjacent to MMP2 sensitive sites and evincing a relatively poor survival rate.
 Conclusion: Overall, this analysis suggested that MMP2 has the capacity of freeing mutant peptides that could facilitate an antitumor response and a better survival rate, and this analysis has the potential of resolving some of the controversy surrounding the role of cancer proteases in cancer progression.
 Citation Format: Saif Zaman, Boris I. Chobrutskiy, Jay S. Patel, Blake M. Callahan, Moody Mihyu, Andrea Diviney, Wei Lue Tong, George Blanck. Potential neoantigen release and increased lymphocyte activity is facilitated by matrix metalloproteinase-dependent cleavage of mutant matrisome peptides in cutaneous melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B12.