Newly identified form of phenotypic plasticity of cancer: immunogenic mimicry

Abstract

Cancer plasticity is now a recognized new hallmark of cancer which is due to disturbances of cell differentiation programs. It is manifested not only in various forms like the best-known epithelial-mesenchymal transition (EMT) but also in vasculogenic and megakaryocytic mimicries regulated by EMT-specific or less-specific transcription factors such as HIF1a or STAT1/2. Studies in the past decades provided ample data that cancer plasticity can be manifested also in the expression of a vast array of immune cell genes; best-known examples are PDL1/CD274, CD47, or IDO, and we termed it immunogenic mimicry (IGM). However, unlike other types of plasticities which are epigenetically regulated, expression of IGM genes are frequently due to gene amplifications. It is important that the majority of the IGM genes are regulated by interferons (IFNs) suggesting that their protein expressions are regulated by the immune microenvironment. Most of the IGM genes have been shown to be involved in immune escape of cancers broadening the repertoire of these mechanisms and offering novel targets for immunotherapeutics.

Keywords: Cancer plasticity; Epithelial mesenchymal transition; Immunogenic mimicry; Megakaryocytic mimicry; Vasculogenic mimicry.

Fig. 1

Schematic presentation of tumor cell-endothelial cell interaction during extravasation. Cancer cells express on their plasma membrane hypersialylated receptors, CD24, CD44, and P-selectin ligand-1 (PSGL-1) to dock on endothelial cell’s E-selectin. In a second step fibrinogen (FBG), receptor integrin avβ3 on both cell types stabilizes the interaction and promotes transendothelial migration

Fig. 2

Schematic presentation of the four major forms of tumor cell mimicries: EMT (epithelial-mesenchymal transition), VM (vasculogenic mimicry), MKM (megakaryocytic mimicry), and IGM (immunogenic mimicry). Basic alterations of EMT are cadherin (CDH) switch from 1-(E) to 2-(N) and cytokeratin (CK) switch to vimentin (vim) in cancer cells. Vasculogenic mimicry (VM) involves also cadherin switch from 1-(E) to 5-(VEcadherin) as well as expression of TIE1 and EphA2 receptors on cancer cells. Megakaryocytic mimicry (MKM) involves ectopic expression of PECAM and CD41/αIIb on cancer cells promoting interactions with platelets (ptl). Immunogenic mimicry (IGM) involves ectopic expression of various immune cell genes in cancer cells, the majority of which generate inhibitory signals resulting in immune escape: CD274/PDL1, CD152/CTLA4, CD47/CD152, CD36, CD40, CD166 (ALCAM), CD276, and IDO1. DC, dendritic cell; MPH, macrophage