Melanocyte PDL1 inhibits MITF expression to maintain low lysosomal activity, associated with promoting NRAS mutant melanoma lung metastases 2725

Description Melanoma is a highly aggressive skin cancer with a strong propensity for lung metastases. We investigated the role of melanocyte PDL1 in facilitating lung metastasis. Using mice with TNQ61R-mutant melanocyte-specific PDL1 deletion (PDL1KO TNQ61R) and littermate controls (PDL1+/+ TNQ61R), tumors were induced with 4-OH tamoxifen ± UVB. While UVB (4.5 kJ/m2) abrogated PDL1 effect on primary tumor latency, lung metastasis remained significantly higher in PDL1+/+ TNQ61R mice, suggesting a distinct role for PDL1 in metastases. Autochthonous PDL1+/+ TNQ61R tumors had lower expression of MITF, a transcription factor critical for primary tumor growth but inhibitory for metastasis, versus autochthonous PDL1KO tumors. NCH1 is a transplantable PDL1+ line from this model. We challenged WT mice SQ with NCH1 and recovered tumors from skin and lung metastases to develop a new, highly lung-metastatic NCH1 subline (NCH1Lu) versus the primary (NCH1P) cell line. We challenged these into WT mice and found that NCH1Lu cells had enhanced lung metastases, increased EMT (vimentin), and reduced MITF vs NCH1P. Genetic PDL1KO in NCH1Lu cells elevated MITF, reduced invasive capacity, and increased lysosomal activity, implicating tumor PDL1 in promoting metastasis by suppressing MITF, maintaining low lysosomal activity and promoting EMT. These findings underscore the pivotal role of melanoma PDL1 signaling in NRASQ61R mutant lung metastasis and show a novel regulatory effect of tumor PDL1 on MITF.