Immune checkpoint inhibitors, including the monoclonal antibody inhibitors of PD1 and CTLA4 have significantly improved outcomes of patients with advanced metastatic melanoma. The CheckMate 067 and KEYNOTE-006 Phase III clinical trials with PD1 inhibitors in melanoma reported objective response rates of 45% and a 5-year overall survival of 39-44%. Response rates and duration can be further extended when PD1 inhibitors are used in combination with the CTLA4 inhibitor, ipilimumab. Despite durability of response, innate resistance to PD-1 inhibition occurs in 30% of melanoma patients and approximately 25% of responding patients will develop acquired resistance within two years of PD-1 inhibitor treatment
The mechanisms responsible for failure of PD-1 inhibition are incompletely understood, although resistance effectors have been identified in a small subset of patients. These include the expression of alternate immune checkpoint inhibitors (TIM-3 and LAG-3), loss of major histocompatibility complex (MHC) class I expression, abnormalities that suppress the IFNg immune effector signalling pathway and oncogenic signalling that leads to immune exclusion or immunosuppression.
We examined tumour-specific mechanisms of immunotherapy resistance in a large panel of melanoma cell models derived from melanoma patients progressing on PD-1 inhibitors, either alone or in combination with CTLA4 inhibitors. Our analysis revealed multiple mechanisms affecting MHC-I and MHC-II antigen presentation whereas loss of IFNg signalling was uncommon. However, we found that melanoma cells frequently showed constitutive IFNg signalling along with diminished responses to exogenous IFNg. These features may contribute to immunotherapy escape by coordinating the expression of an immune suppressive melanoma phenotype with diminished antigen production.