MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma

Abstract

Combination anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1) therapy promotes antitumor immunity and provides superior benefit to patients with advanced-stage melanoma compared with either therapy alone. T cell immunity requires recognition of antigens in the context of major histocompatibility complex (MHC) class I and class II proteins by CD8 and CD4 T cells, respectively. We examined MHC class I and class II protein expression on tumor cells from previously untreated melanoma patients and correlated the results with transcriptional and genomic analyses and with clinical response to anti-CTLA-4, anti-PD-1, or combination therapy. Most (>50% of cells) or complete loss of melanoma MHC class I membrane expression was observed in 78 of 181 cases (43%), was associated with transcriptional repression of ,, , and, and predicted primary resistance to anti-CTLA-4, but not anti-PD-1, therapy. Melanoma MHC class II membrane expression on >1% cells was observed in 55 of 181 cases (30%), was associated with interferon-γ (IFN-γ) and IFN-γ-mediated gene signatures, and predicted response to anti-PD-1, but not anti-CTLA-4, therapy. We conclude that primary response to anti-CTLA-4 requires robust melanoma MHC class I expression. In contrast, primary response to anti-PD-1 is associated with preexisting IFN-γ-mediated immune activation that includes tumor-specific MHC class II expression and components of innate immunity when MHC class I is compromised. The benefits of combined checkpoint blockade may be attributable, in part, to distinct requirements for melanoma-specific antigen presentation to initiate antitumor immunity.

Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma

“…This is in line with recent observations that PD-L1 ( CD274 ) is a BCL6-supressed gene 41 , and a well-characterized role for PD-L1 as an IFN-γ-responsive gene 40 . In other cancers in which a florid antigen-driven immune response and concomitant adaptive immune suppression via PD-L1 exist within the tumor microenvironment, blockade of the PD-1 receptor is an effective therapeutic strategy 13,15 . In support of this, recent studies have shown that the efficacy of PD-1 blockade is inextricably linked with the existence of an interferon-driven immune response and expression of MHC class II 13,15 .…”

“…In other cancers in which a florid antigen-driven immune response and concomitant adaptive immune suppression via PD-L1 exist within the tumor microenvironment, blockade of the PD-1 receptor is an effective therapeutic strategy 13,15 . In support of this, recent studies have shown that the efficacy of PD-1 blockade is inextricably linked with the existence of an interferon-driven immune response and expression of MHC class II 13,15 . Together, these observations suggest that the greatest potentiation of anti-tumor immunity in GCB-derived malignancies may be achieved through stimulation of interferon signaling and MHC class II expression by HDAC3 inhibition, in combination with the inhibition of adaptive immune suppression using PD-L1/PD-1 neutralizing antibodies.…”

“…Recently, MHC class II expression has been defined as an important component of interferon-gamma (IFN-γ) related signatures that are predictive of the activity of PD-1 neutralizing antibodies 13-15 . This is consistent with a prominent role for CD4 T-cells in directing anti-tumor immunity and responses to immunotherapy 16 .…”

Immune checkpoint inhibitors for head and neck squamous cell carcinoma: Current landscape and future directions

“…For example, angiogenesis signature can predict the clinical response to atezolizumab‐bevacizumab combination therapy in renal cell carcinoma . In melanoma, MHC protein expression can predict differential activity to anti‐CTLA4 or anti‐PD1 . Development of a universal biomarker platform for HNSCC treatment, including immunotherapy, is becoming increasingly essential for guiding personalized therapy.…”

“…88 In melanoma, MHC protein expression can predict differential activity to anti-CTLA4 or anti-PD1. 89 Development of a universal biomarker platform for HNSCC treatment, including immunotherapy, is becoming increasingly essential for guiding personalized therapy. Human papillomavirus (HPV) associated oropharyngeal carcinoma is considered as a malignancy with better prognosis.…”