The DUMMER Lines: An NRASQ61R-mutant melanoma cell line library to study roles of melanoma cell-of-origin (melanocyte) PDL1 and UVB exposure in melanoma signaling, treatment resistance, and metastasis 3211

Description Ultraviolet B (UVB) exposure is associated with NrasQ61R mutations that drive melanomagenesis. UVB-associated melanomas tend to be more aggressive, metastatic, and treatment-resistant vs. other melanomas. We generated an inducible, UVB-accelerable NRASQ61R-mutant mouse melanoma model with (CTRL) or without melanocyte PDL1 (melPDL1KO) and created a library of transplantable Dartmouth & UTHSA Mouse Melanoma Exposed to Radiation (DUMMER) cell lines. DUMMER lines model PDL1 deletion from the tumor cell-of-origin to study bona-fide melanoma cell-intrinsic PDL1 signals in UVB-driven melanomagenesis, treatment resistance, and metastasis. MelPDL1 promotes in vitro tumor proliferation and pro-tumorigenic mTORC1 signaling, consistent with our prior work in tumor-intrinsic roles of PDL1 in B16, and mediates resistance to MAPK inhibition. Other melPDL1- and/or prior UVB exposure-dependent effects were noted. UVB-induced DUMMER lines resist in vitro MEK and PARP inhibition vs. UVB naïve lines, differ in type I IFN signals, and are highly metastatic. Autochthonous melPDL1KO lines were αPDL1-resistant in vivo vs. sensitive genetic PDL1KO lines made from PDL1+ DUMMER lines and differed in TIL composition. Thus, melPDL1 has important and irreversible roles in tumorigenesis and ICB resistance. The DUMMER lines present a useful tool for melanoma research and will contribute significantly to determining how melPDL1 and UVB are immunopathogenic and drive metastasis and treatment resistance. Funding Sources NIH T32GM113896 (STX MSTP) Award (C.O. and C.M.) and the NCI F31CA281345 (C.O.). NCI (CA252057, CA268641, CA246707, CA292467), Gmelich chair and Guyre funds supported Curiel. Work was supported by the Dartmouth Cancer Center and DartLab, the Immune Monitoring and Flow Cytometry Shared Resource at the Dartmouth Cancer Center, with NCI Cancer Center Support Grant 5P30 CA023108-41.