Figure 2.

Tumor mechanisms of subversion of immune cell infiltration within the TME. The panels show several mechanisms, discussed in the text, adopted by tumor or tumor-associated cells to evade effector immune cell infiltration. The legends at the top of each panel illustrate the specific structures and molecules involved in each mechanism. Cell movements are represented as dashed arrows. (a) TAM-driven secretion of VEGF can reduce the expression of vascular VE-cadherin, causing transient and local leakiness. TAM VLA-4 interaction with VCAM-1 on vascular endothelial cells favors further TAM diapedesis. (b) Loss of MHC-I expression due to CAF-secreted TGF-β makes tumors less visible to the immune system, affecting effector T cell infiltration and tumor control. (c) TGF-β produced by TAMs or CAFs enhances the expression of CCR4 in Tregs, whereas it decreases the CXCR3 expression on CD8 T cells, thus promoting the infiltration of the first ones over the latter. CAF and/or MDSC secrete CXCL12 and CCL2 to recruit TAMs and monocytes, respectively, in the TME. (d) MDSCs production of NO downregulates the expression of CD44 and P/E selectin, impairing effector T cell extravasation and tumor infiltration. Higher expression of LFA-1 integrin on the surface of Tregs favors their interaction with APCs, leading to decreased activation of effector CD8+ T cells. Increased expression of CLEVER-1 (see Section: Mechanisms of Subversion of Adhesion Molecules) on the surface of vascular endothelial cells promotes Tregs diapedesis through ICAM-1 in the TME. (e) CAF deposition of collagen and other ECM components increases the tumor stiffness, hindering effector T cell migration and distribution within the TME. CAF organization with stroma cells in desmoplastic reactions surrounding tumor cells creates a physical obstacle limiting effector immune cell trafficking.