Abstract
Epithelial-mesenchymal plasticity (EMP) of cancer cells contributes to cancer cell heterogeneity, and it is well established that EMP is a critical determinant of acquired resistance to cancer treatment modalities including radiation therapy, chemotherapy, and targeted therapies. Here, we aimed to explore how EMP contributes to cancer cell camouflage, allowing an ever-changing population of cancer cells to pass under the radar of our immune system and consequently compromise the effect of immune checkpoint blockade therapies. The ultimate clinical benefit of any combination regimen is evidenced by the sum of the drug-induced alterations observed in the variety of cellular populations composing the tumor immune microenvironment. The finely-tuned molecular crosstalk between cancer and immune cells remains to be fully elucidated, particularly for the spectrum of malignant cells along the epithelial to mesenchymal axis. High-dimensional single cell analyses of specimens collected in ongoing clinical studies is becoming a key contributor to our understanding of these interactions. This review will explore to what extent targeting EMP in combination with immune checkpoint inhibition represents a promising therapeutic avenue within the overarching strategy to reactivate a halting cancer-immunity cycle and establish a robust host immune response against cancer cells. Therapeutic strategies currently in clinical development will be discussed.
Highlights
The early history of cancer immunotherapyThe history of cancer immunology research dates all the way back to 1863 when Rudolf Virchow observed immune cell infiltration in tumors and hypothesized that sites of chronic inflammation served as a hot bed for cancer development[1,2]
We have recently shown that the small molecule AXL inhibitor bemcentinib abrogates the autophagic flux and is a potent inducer of immunogenic cell death (ICD); this is of particular interest as it implicates a favorable adjuvant effect and alteration of the tumor immune microenvironment (TIME) upon AXL inhibition in immunogenic but immunosuppressed tumors[53,124]
Rather than prevention, of Epithelial-mesenchymal plasticity (EMP) is being tested in most current clinical trials [Table 1], for most compounds, the optimal strategy would be to move from secondline combination testing to 1st line combination with immune checkpoint blockade (ICB)
Summary
The history of cancer immunology research dates all the way back to 1863 when Rudolf Virchow observed immune cell infiltration in tumors and hypothesized that sites of chronic inflammation served as a hot bed for cancer development[1,2]. Antibodies blocking the PD-1/PD-L1 axis have been shown to induce durable clinical responses in numerous cancer types including malignant melanoma[22,23,32], non-small cell lung cancer (NSCLC)[33,34], urothelial carcinoma[35,36], head and neck squamous cell carcinoma, Hodgkin’s lymphoma and renal cell carcinoma (RCC)[32,33,34,37,38,39] This has led to FDA approval of several immune checkpoint inhibitors including the fully humanized monoclonal PD-. We aim to elucidate how EMP affects the various steps of the cancer-immunity cycle and to highlight some of the clinical evidence and molecular mechanisms supporting the hypothesis that targeting EMP represents a promising therapeutic avenue within the overarching strategy to reactivate a halting cancer-immunity cycle and establish a robust host immune response against cancer cells
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