Decoding cancer's camouflage: epithelial-mesenchymal plasticity in resistance to immune checkpoint blockade

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.

Keywords: Epithelial-to-mesenchymal transition; epithelial-mesenchymal plasticity; immune evasion; intrinsic and extrinsic mechanisms of resistance to immune checkpoint blockade; therapeutic opportunity; tumor immune microenvironment.

Figure 1

EMP affects various steps of the cancer-immunity cycle. The therapeutic rationale for targeting EMP in combination with ICB is based on the fact that EMP affects multiple steps of the cancer-immunity cycle described by Chen and Mellman^[117]. Briefly, targeting EMP can induce an increased release of DAMPs serving as an adjuvant during the release of cancer cell antigens (STEP 1). DAMPs are further recognized by pattern recognition receptors (PRRs) including TLRs. EMP targeting can induce an M1 to M2 polarization of macrophages and an activation of APCs, and thus aid in cancer antigen presentation (STEP 2). Targeting EMP and the EMP-associated immunosuppressive tumor immune microenvironment (TIME) can enable the infiltration of educated T cells into the cancer (STEP 5). EMP is associated with reduced recognition (STEP 6) and immune effector cell-mediated killing (STEP 7) of cancer cells, and targeting EMP can therefore induce increased effector cell-mediated lysis of cancer cells and propagation of the cycle. Adapted courtesy of Chen and Mellman^[117]. EMP: epithelial-mesenchymal plasticity; ICB: immune checkpoint blockade; DAMPs: damage-associated molecular patterns; APCs: antigen-presenting cells