MMP2 is a immunotherapy related biomarker and correlated with cancer-associated fibroblasts infiltrate in melanoma

Abstract

BackgroundMounting evidence supports that matrix metalloproteinase (MMPs) are highly associated with tumor progression and that targeting MMPs may overcome the barrier of immune suppression. Among these, whether MMP2 functions as an immunosuppressive role in melanoma, remains unclear.MethodsThe Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) databases were used to assess the prognosis of MMP2 in melanoma, after which Tumor immune estimation resource (TIMER) was used to explore the relationship between MMP2 expression and cancer associated fibroblasts (CAFs) infiltration. Finally, we evaluated the efficacy of MMP2 inhibitor on CAFs infiltration and immunotherapy using a mouse melanoma model.ResultsIn general, the expression of MMP2, MMP13, MMP16, MMP17 and MMP25 were significantly associated with skin cutaneous melanoma (SKCM) patients prognosis, among which MMP2 low expression benefited patients the most. Especially, the overall survival (OS) of BRAF mutation patients with high MMP2 expression was significantly lower than the MMP2 low expression group, but there was no significant difference in BRAF wild-type patients. KEGG and GO enrichment analysis indicated that MMP2 related genes were mostly associated with extracellular structure organization, collagen-containing extracellular matrix and extracellular matrix structural constituent. Furthermore, in almost all cancers, MMP2 expression was positively correlated with CAFs infiltration. MMP2 inhibitor works synergistically with PD-1 antibody and induces tumor regression in a mouse melanoma model, which is dependent on decreased CAFs infiltration.ConclusionsThis suggests that MMP2 plays a vital role in the regulation of CAFs infiltration, potentially participating in immunotherapy response, and thus representing a valuable target of immunotherapy in melanoma.