Modelling major histocompatibility class I (MHC-I) deficiency and immunotherapy response in a mouse model of melanoma

The treatment of advanced melanoma has significantly improved with the use of immunotherapies that inhibit the checkpoint proteins, programmed cell death protein 1 (PD-1) and cytotoxic Tlymphocyte- associated antigen 4 (CTLA-4). Approximately 60% of melanoma patients will respond to the combination of PD-1 and CTLA-4 blockade. Despite these advances, 40% of patient will not respond to combination immunotherapy and 25% of responding patients will develop resistance. Several mechanisms of resistance to immunotherapies have been described, including the downregulation of the major histocompatibility complex (MHC) class I. MHC-I is expressed on tumour cells and displays tumour neoantigen peptides to T cells. The recognition of peptide- MHC-I complexes by CD8 cytotoxic T cells triggers their activation and an anti-tumour immune response. These immune responses can be dampened when tumour cells downregulate the expression of MHC-I antigen presentation molecules. The precise impact of MHC-I downregulation on patient responses to immune checkpoint inhibitors remains unclear, however, with evidence that MHC-I loss does not preclude patient response to combination immune checkpoint inhibition. 

In this project the effect of tumour MHC-I loss on immunotherapy response was investigated. MHC-I deficient mouse melanoma cells were generated and compared to matched, parental MHCI intact melanoma cell lines. Functional and phenotypic analyses were performed and response to PD-1 inhibitor monotherapy and combined (PD-1 plus CTLA-4 inhibition) was examined. We now confirm that MHC-I deficient melanoma tumours are not responsive to anti-PD-1 based monotherapy but show limited response to combined immunotherapy. In response to combined PD-1 and CTLA-4 blockade, MHC-I deficient melanoma showed evidence of immune activity, primarily through increased infiltration of CD4 T helper cells. These immunotherapy-dependent changes may provide an opportunity to develop novel therapeutic strategies that stimulate the existing, albeit, limited immune activity seen in MHC-I deficient melanoma.