Loss of MHC-I antigen presentation correlated with immune checkpoint blockade tolerance in MAPK inhibitor-resistant melanoma

Abstract

Immune checkpoint blockade and MAPK-targeted combined therapy is a promising regimen for advanced melanoma patients. However, the clinical benefit from this combo regimen remains limited, especially in patients who acquired resistance to MAPK-targeted therapy. Here, we systematically characterized the immune landscape during MAPK-targeted therapy in patients and mouse melanoma models. We observed that both the abundance of tumor-infiltrated T cells and the expression of immune-related genes were upregulated in the drug-responsive period, but downregulated in the resistance period, implying that acquired drug resistance dampens the antitumor immune response. Further transcriptomic dissection indicated that loss of MHC-I antigen presentation on tumor cells plays a critical role in the reduction of T cell infiltration during drug resistance. Survival analysis demonstrates that loss of antigen presentation and reduction of T-cell infiltration during acquired drug resistance are associated with poorer clinical response and prognosis of anti-PD-1 therapy in melanoma patients. In addition, we identified that alterations in the MAPK inhibitor resistance-related oncogenic signaling pathway closely correlated with deficiency of MHC-I antigen presentation, including activation of the PI3K-mTOR, MAPK, and Wnt pathways. In conclusion, our research illuminates that decreased infiltration of T cells is associated with acquired drug resistance during MAPK-targeted therapy, which may underlie the cross-resistance to immune checkpoint blockade.

Photothermally sensitive gold nanocage augments the antitumor efficiency of immune checkpoint blockade in immune “cold” tumors

“…Therapeutic antibodies that block the PD-1/PD-L1 pathway can induce continuous and powerful reactions in patients with various cancers, however, only a subset of patients benefit from this treatment regimen. The tremendous hurdle for ICB lies in insufficient tumor antigen presentation which leads to limited T cells in the tumor microenvironment (namely, an immune “cold” tumor) ( 41 , 45 , 46 ). In order to improve the efficacy of ICB and reprogram a “cold” immune microenvironment into a “hot” one, finding a simple and safe method to increase the number of infiltrating T cells and promote the release of tumor antigens is important.…”

Programmed cell death‐1 blockade therapy in melanoma: Resistance mechanisms and combination strategies

“…Losing or down-regulating MHC-I/II expression will impair the antigen presenting capacity so as to reduce T cell infiltration and escape immune surveillance. [7][8][9][10][11] If there is a mutation of the beta-2-microglobulin gene, which encodes a component of the MHC-I molecule, tumor-specific CD8 + T cells will fail to recognize tumor cells, leading to immune escape 12,13 (Figure 1A). Besides gene mutation, melanoma dedifferentiation with up-regulated AXL receptor tyrosine kinase and down-regulated micropthalmia-associated transcription factor (MITF) driven by stromal transforming growth factorβ (TGFβ), or activated activating transcription factor 4 (ATF4) regulated by tumor necrosis factor α (TNFα), are other mechanisms to lower MHC expression and mediate melanoma invasion.…”

“…Antigens presented by tumor cells through the major histocompatibility complex (MHC) can be recognized by tumor‐specific T cells, activating the immune response. Losing or down‐regulating MHC‐I/II expression will impair the antigen presenting capacity so as to reduce T cell infiltration and escape immune surveillance 7–11 . If there is a mutation of the beta‐2‐microglobulin gene, which encodes a component of the MHC‐I molecule, tumor‐specific CD8 + T cells will fail to recognize tumor cells, leading to immune escape 12,13 (Figure 1A).…”

Integrative analysis of single-cell and bulk RNA sequencing unveils a machine learning-based pan-cancer major histocompatibility complex-related signature for predicting immunotherapy efficacy

“…Primary response to anti-CTLA-4 requires robust melanoma MHC class I expression and 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 [ 7 ]. Loss of MHC class I antigen presentation on tumor cells plays a critical role in the reduction of T cell infiltration during drug resistance [ 8 ]. MHC class I-mediated antigen presentation by Hodgkin Reed-Sternberg cells is an important component of the biological response to standard chemo/radiotherapy [ 9 ] and genetically driven PD-L1 expression and MHC class II positivity on Hodgkin Reed-Sternberg cells are potential predictors of favorable outcomes after PD-1 blockade [ 10 ].…”