Lee et al. demonstrated that none of a set of seven previously reported transcriptomic signatures associated with clinical response to PD-1 inhibition from single-point pretreatment biopsies predicted response to PD-1 inhibitor monotherapy in a cohort of 44 melanoma patients and in three other RNASeq datasets. Tumors resistant to PD-1 monotherapy demonstrated MHC class I downregulation, which was associated with SNAI1 upregulation, CAF signatures, and an MITFlow/AXLhigh de-differentiation phenotype, and has implications for subsequent therapy. TGFβ signaling contributed to MHC class I downregulation.
Contributed by Shishir Pant
ABSTRACT: Transcriptomic signatures designed to predict melanoma patient responses to PD-1 blockade have been reported but rarely validated. We now show that intra-patient heterogeneity of tumor responses to PD-1 inhibition limit the predictive performance of these signatures. We reasoned that resistance mechanisms will reflect the tumor microenvironment, and thus we examined PD-1 inhibitor resistance relative to T-cell activity in 94 melanoma tumors collected at baseline and at time of PD-1 inhibitor progression. Tumors were analyzed using RNA sequencing and flow cytometry, and validated functionally. These analyses confirm that major histocompatibility complex (MHC) class I downregulation is a hallmark of resistance to PD-1 inhibitors and is associated with the MITF(low)/AXL(high) de-differentiated phenotype and cancer-associated fibroblast signatures. We demonstrate that TGFss drives the treatment resistant phenotype (MITF(low)/AXL(high)) and contributes to MHC class I downregulation in melanoma. Combinations of anti-PD-1 with drugs that target the TGFss signaling pathway and/or which reverse melanoma de-differentiation may be effective future therapeutic strategies.
Author Info: (1) Macquarie University, Sydney, NSW, Australia. Melanoma Institute Australia, Sydney, NSW, Australia. Chris O'Brien Lifehouse, Camperdown, NSW, Australia. (2) Macquarie Universit
Author Info: (1) Macquarie University, Sydney, NSW, Australia. Melanoma Institute Australia, Sydney, NSW, Australia. Chris O'Brien Lifehouse, Camperdown, NSW, Australia. (2) Macquarie University, Sydney, NSW, Australia. Melanoma Institute Australia, Sydney, NSW, Australia. (3) Macquarie University, Sydney, NSW, Australia. Melanoma Institute Australia, Sydney, NSW, Australia. (4) Melanoma Institute Australia, Sydney, NSW, Australia. Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, NSW, Australia. (5) Melanoma Institute Australia, Sydney, NSW, Australia. Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, NSW, Australia. (6) Macquarie University, Sydney, NSW, Australia. Melanoma Institute Australia, Sydney, NSW, Australia. (7) Macquarie University, Sydney, NSW, Australia. Melanoma Institute Australia, Sydney, NSW, Australia. (8) Macquarie University, Sydney, NSW, Australia. Melanoma Institute Australia, Sydney, NSW, Australia. (9) Melanoma Institute Australia, Sydney, NSW, Australia. Melanoma Oncology and Immunology, Centenary Institute, Camperdown, NSW, Australia. (10) School of Mathematics and Statistics, The University of Sydney, Sydney, NSW, Australia. Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia. (11) School of Mathematics and Statistics, The University of Sydney, Sydney, NSW, Australia. Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia. (12) Melanoma Institute Australia, Sydney, NSW, Australia. Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia. Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. (13) Melanoma Institute Australia, Sydney, NSW, Australia. Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia. Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. (14) Melanoma Institute Australia, Sydney, NSW, Australia. Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia. Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. (15) Melanoma Institute Australia, Sydney, NSW, Australia. Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia. Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia. (16) Melanoma Institute Australia, Sydney, NSW, Australia. Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, NSW, Australia. Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia. Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. (17) Macquarie University, Sydney, NSW, Australia. Melanoma Institute Australia, Sydney, NSW, Australia. (18) Macquarie University, Sydney, NSW, Australia. helen.rizos@mq.edu.au. Melanoma Institute Australia, Sydney, NSW, Australia. helen.rizos@mq.edu.au.
