Abstract 6078: Suppression of tumor-intrinsic IFNγ signaling in ARF6-mediated metastatic progression of melanoma

Abstract

Abstract ARF6 is a small GTPase that controls the subcellular location of proteins to regulate invasion, proliferation and tumor microvesicle shedding. ARF6 is aberrantly activated in cutaneous melanoma and stimulates invasion in BRAFV600E-melanoma by controlling localization and activation of beta-catenin and PI3K/AKT. In uveal melanoma, ARF6 facilitates GNAQQ209L signaling to drive tumor growth by trafficking GNAQ to cytoplasmic vesicles. Although distinct diseases, pharmacologic inhibition of ARF6 reduces disease progression in both uveal and cutaneous melanoma models. These data underscore the importance of intracellular trafficking mechanisms in cancer and highlight the potential clinical utility of targeting this machinery by inhibiting ARF6. In order to genetically dissect the role of ARF6 in melanomagenesis, we utilized RCAS-mediated delivery of Cre recombinase, with or without constitutively activated ARF6 (Arf6Q67L), specifically to melanocytic cells to induce constitutive activation of BRAFV600E (BrafCA), deletion of Cdkn2a (Cdkn2af/f) and (Arf6f/f). Activation of ARF6 accelerates spontaneous metastasis while loss of Arf6 delays tumor onset and reduces tumor incidence and growth, dramatically improving survival of BrafCA;Cdkn2af/f mice, including in the presence of Pten loss. Unexpectedly, tumors expressing ARF6Q67L show significantly reduced expression of interferon-gamma (IFNγ) response genes, reduced CD8 (T cell) transcripts and an anti-apoptotic proteomics profile. Knockdown of Arf6 sensitizes BRAFV600E melanoma cells to IFNγ treatment reducing cell viability in vitro. Together these data demonstrate that ARF6 modulates BRAFV600E-driven tumor progression and suggest that ARF6 activation suppresses tumor intrinsic IFNγ signaling to evade the anti-tumor immune response during metastatic progression. Our in vivo models provide a new paradigm for understanding vulnerabilities in BRAF-mediated oncogenesis and implicate intracellular trafficking mechanisms as potentially actionable machinery in melanoma development, immune evasion and disease progression. Citation Format: Coulson P. Rich, Aaron Rogers, Jae Hyuk Yoo, Roger Wolff, Shannon J. Odelberg, Sheri L. Holmen, Allie H. Grossmann. Suppression of tumor-intrinsic IFNγ signaling in ARF6-mediated metastatic progression of melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6078.