Do Tumor Mechanical Stresses Promote Cancer Immune Escape?

Abstract

Immune evasion-a well-established cancer hallmark-is a major barrier to immunotherapy efficacy. While the molecular mechanisms and biological consequences underpinning immune evasion are largely known, the role of tissue mechanical stresses in these processes warrants further investigation. The tumor microenvironment (TME) features physical abnormalities (notably, increased fluid and solid pressures applied both inside and outside the TME) that drive cancer mechanopathologies. Strikingly, in response to these mechanical stresses, cancer cells upregulate canonical immune evasion mechanisms, including epithelial-mesenchymal transition (EMT) and autophagy. Consideration and characterization of the origins and consequences of tumor mechanical stresses in the TME may yield novel strategies to combat immunotherapy resistance. In this Perspective, we posit that tumor mechanical stresses-namely fluid shear and solid stresses-induce immune evasion by upregulating EMT and autophagy. In addition to exploring the basis for our hypothesis, we also identify explicit gaps in the field that need to be addressed in order to directly demonstrate the existence and importance of this biophysical relationship. Finally, we propose that reducing or neutralizing fluid shear stress and solid stress-induced cancer immune escape may improve immunotherapy outcomes.

Keywords: autophagy; epithelial–mesenchymal transition; fluid shear stress; immune evasion; immunotherapy; interstitial fluid pressure; solid stress; solid tumors.

Figure 1

The physical and biological characteristics of tumors and their microenvironment interact to influence immune evasion and immunotherapy outcomes. Mechanical stress (solid and fluid) can exert both direct and indirect effects to promote immune evasive mechanisms. In tumors, solid stress (compressive and tensile) collapses tumor blood vessels, causing hypoxia within the TME, and induces EMT and autophagy within cancer cells via the activation of pathways responsible for mesenchymal transition and invasiveness [6,7,8,9,10,11,12]. The solid stress-induced activation of other pathways (e.g., VEGF) in turn enhances PD-1 expression and the recruitment of Tregs and MDSCs, thus promoting immunosuppression [13,14]. In the presence of fluid components within the TME, and during circulation, cancer cells experience increased fluid shear stress, which can directly enhance and support immune evasion via the recruitment of MDSCs and upregulation of PD-L1 [15,16,17,18,19,20]. Shear stress also induces EMT and autophagy mechanisms by promoting cytoskeletal rearrangement and the formation of autophagosomes [21,22,23,24]. The mechanical induction of EMT and autophagy by solid and shear stresses may mediate cancer immune escape via variable mechanisms that have yet to be directly tested, though indirect evidence exists that suggests that some of the following phenomena may be involved. EMT inhibits the CTL-mediated killing of malignant cells and promotes immune evasion due to increased resistance to CTL-activated death receptor pathways and the enhanced expression of PD-L1 [25,26,27]. Autophagy also supports immune evasion via the degradation of MHC-I and granzyme B, and the upregulation of pSTAT3 [28,29,30]. Interplay between EMT and autophagy influences immune evasion, although this remains controversial [31,32]. We postulate that this collective contribution of aberrant tumor mechanical stresses on immunological responses may inhibit immunotherapy efficacy.