Abstract 5025: Immune expression profiling of MAPK inhibitor resistant tumors based upon mechanisms of resistance

Abstract

Abstract Purpose: To evaluate the association between the immunoreactivity of the immune inhibitory ligand PD-L1 with tumour infiltrating lymphocytes (TILs) and known mechanisms of MAPK inhibitor (MAPKi) resistance in tumor biopsies resected at the time of MAPKi disease progression. Experimental Design: 23 patients with disease progression on MAPKi (vemurafenib, dabrafenib, and combination dabrafenib and trametinib) each had a progressing tumor biospied. All tumors underwent MAPKi resistance screening including RNA expression profiling. Morphological features, PD-L1 immunohistochemical immunoreactivity, and RNA expression profile were correlated with mechanisms of resistance (including mutations in NRAS and MEK, and amplification and aberrant splicing of BRAF). Results: PD-L1 immunoreactivity was significantly higher in tumors that harbored an aberrant BRAF splicing variant (n = 8) or MEK mutations (n = 5) than those with BRAF amplification (n = 4), NRAS mutations (n = 2) or those with unknown resistance mechanisms (n = 4) (mean 27% vs 1%, p = 0.049). Additionally, the PD-L1 immunoreactivity in tumors with known MAPK-reactivating mechanisms (n = 19) tended to be higher than those with unknown resistance mechanisms (n = 4) (mean 17% vs 0%, p = 0.283). The immunoreactivity of PDL1 in progressed lesions was independent of BRAFV600 genotype, RECIST response and type of MAPK inhibitor. Correlations with TIL subsets, RNA expression, and response to subsequent anti-PD-1 therapy are underway. Conclusions: The induction of PD-L1 immunoreactivity following MAPKi treatment in human melanoma is variable, however specific mechanisms of MAPKi resistance may confer increased expression of the inhibitory ligand. Further study is underway examining the association of the above with TIL infiltration, the RNA expression profile, and the response to subsequent anti-PD1 therapy. Citation Format: James S. Wilmott, Hojabr Kakavand, Alexander M. Menzies, Ricardo Vilain, Gulietta M. Pupo, John F. Thompson, Richard F. Kefford, Matteo S. Carlino, Helen Rizos, Georgina V. Long, Richard A. Scolyer. Immune expression profiling of MAPK inhibitor resistant tumors based upon mechanisms of resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5025. doi:10.1158/1538-7445.AM2015-5025