Indicators of responsiveness to immune checkpoint inhibitors

Abstract

Modulation of the immune system can produce anti-tumor responses in various cancer types, including melanoma. Recently, immune checkpoint inhibitors (ICI), in single agent and combination regimens, have produced durable and long-lasting clinical responses in a subset of metastatic melanoma patients. These monoclonal antibodies, developed against CTLA-4 and PD-1, block immune-inhibitory receptors on activated T-cells, amplifying the immune response. However, even when using anti-CTLA-4 and anti-PD-1 in combination, approximately half of patients exhibit innate resistance and suffer from disease progression. Currently, it is impossible to predict therapeutic response. Here, we report the first proteomic and histone epigenetic analysis of patient metastatic melanoma tumors taken prior to checkpoint blockade, which revealed biological signatures that can stratify patients as responders or non-responders. Furthermore, our findings provide evidence of mesenchymal transition, a known mechanism of immune-escape, in non-responding melanoma tumors. We identified elevated histone H3 lysine (27) trimethylation (H3K27me3), decreased E-cadherin, and other protein features indicating a more mesenchymal phenotype in non-responding tumors. Our results have implications for checkpoint inhibitor therapy as patient specific responsiveness can be predicted through readily assayable proteins and histone epigenetic marks, and pathways activated in non-responders have been identified for therapeutic development to enhance responsiveness.

Mesenchymal traits at the convergence of tumor-intrinsic and -extrinsic mechanisms of resistance to immune checkpoint blockers

“…That ECM composition and remodeling play a key role in mediating response to ICBs is also confirmed by the signatures of resistance to ICBs that evidence the up-regulation of ECM components or factors that contribute to ECM remodeling [19][20][21].…”

“…The proteomic analysis of formalin-fixed, paraffin-embedded metastatic melanoma tissues collected prior ICBs evidenced 106 significantly different proteins between responding and non-responding groups [19]. The analysis showed that non-responding tumors were characterized by elevated histone H3 lysine [27] trimethylation (H3K27me3) and decreased E-cadherin, features related to a more mesenchymal phenotype.…”

“…Recently, the importance of integrating tumor classification with an 'EMT score' has highlighted the need to consider the contribution of the rich stromal contingent present within the TME to better define the mesenchymal status of a tumor [22]. This is a crucial node to interpret, in light of the different genomic and proteomic signatures that have evidenced tumor mesenchymal traits associated with an immunosuppressive TME and resistance to ICBs [19][20][21].…”

“…Of clinical relevance in the new era of immune checkpoint blockers (ICBs), tumor-enriched mesenchymal traits have emerged as a signature of resistance [19][20][21][22], whereas the highest objective response rates were observed in cancers with a high mutational load [i.e. melanoma and non-small cell lung cancer (NSCLC)] and are likely related to an enriched tumor-associated antigen (TAA) repertoire [23][24][25][26][27].…”

A randomized, phase 1, placebo‐controlled trial of APG‐157 in oral cancer demonstrates systemic absorption and an inhibitory effect on cytokines and tumor‐associated microbes

“…7E and F). CCL2 expression was correlated with CD3‐positive, CD8‐positive T‐cell infiltration in several studies . CCL2, CXCL5, CXCL8, and CXCL12 are suggested to play a role in monocyte recruitment in the tumor microenvironment, and CCL28 is involved in regulatory T cell recruitment that may be associated with the promotion of immune evasion.…”