New insights into the role of EMT in tumor immune escape

Abstract

Novel immunotherapy approaches have provided durable remission in a significant number of cancer patients with cancers previously considered rapidly lethal. Nonetheless, the high degree of nonresponders, and in some cases the emergence of resistance in patients who do initially respond, represents a significant challenge in the field of cancer immunotherapy. These issues prompt much more extensive studies to better understand how cancer cells escape immune surveillance and resist immune attacks. Here, we review the current knowledge of how cellular heterogeneity and plasticity could be involved in shaping the tumor microenvironment (TME) and in controlling antitumor immunity. Indeed, recent findings have led to increased interest in the mechanisms by which cancer cells undergoing epithelial‐mesenchymal transition (EMT), or oscillating within the EMT spectrum, might contribute to immune escape through multiple routes. This includes shaping of the TME and decreased susceptibility to immune effector cells. Although much remains to be learned on the mechanisms at play, cancer cell clones with mesenchymal features emerging from the TME seem to be primed to face immune attacks by specialized killer cells of the immune system, the natural killer cells, and the cytotoxic T lymphocytes. Recent studies investigating patient tumors have suggested EMT as a candidate predictive marker to be explored for immunotherapy outcome. Promising data also exist on the potential utility of targeting these cancer cell populations to at least partly overcome such resistance. Research is now underway which may lead to considerable progress in optimization of treatments.

Missed Druggable Cancer Hallmark: Cancer–Stroma Symbiotic Crosstalk as Paradigm and Hypothesis for Cancer Therapy

“…The number of CTLA‐4 molecules on the surface of T cells is directly correlated to costimulatory/checkpoint receptors. The literature on this subject is vast, so here I will only refer to the recent concise and systematic reviews, limiting them to the most general concepts. The initial contact of TCRs with the antigen‐loaded MHC on APCs (signal 1) induces the activation of multiple effectors, including membrane‐bound molecules such as integrins, lymphocyte function‐associated antigen‐1 (LFA‐1) and its ligand ICAM‐1, signaling adaptors, cytoskeletal elements, etc.…”

“…Mechanical forces generated at ISs as a result of intercellular adhesion are also important. ISs involving NK cells do not express TCRs, but they express activating and inhibitory receptors that can regulate signaling and dynamic changes in the integrin–actin network . Generally, the current therapies aimed at checkpoint blockade directly affect the immunological synapse .…”

Traditional Chinese medicine as targeted treatment for epithelial‐mesenchymal transition‐induced cancer progression

“…Recent studies of patient tumors have revealed that EMT is a candidate predictive marker for immunotherapy. EMT is a critical process for immune resistance, but it is also a powerful driver of the immune suppression network within the tumor microenvironment . Increasing evidence has also demonstrated a link between cancer‐associated EMT and chronic inflammation .…”

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

“…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].…”