Tumor Extracellular Matrix Stiffness Promptly Modulates the Phenotype and Gene Expression of Infiltrating T Lymphocytes

Abstract

The immune system is a fine modulator of the tumor biology supporting or inhibiting its progression, growth, invasion and conveys the pharmacological treatment effect. Tumors, on their side, have developed escaping mechanisms from the immune system action ranging from the direct secretion of biochemical signals to an indirect reaction, in which the cellular actors of the tumor microenvironment (TME) collaborate to mechanically condition the extracellular matrix (ECM) making it inhospitable to immune cells. TME is composed of several cell lines besides cancer cells, including tumor-associated macrophages, cancer-associated fibroblasts, CD4+ and CD8+ lymphocytes, and innate immunity cells. These populations interface with each other to prepare a conservative response, capable of evading the defense mechanisms implemented by the host's immune system. The presence or absence, in particular, of cytotoxic CD8+ cells in the vicinity of the main tumor mass, is able to predict, respectively, the success or failure of drug therapy. Among various mechanisms of immunescaping, in this study, we characterized the modulation of the phenotypic profile of CD4+ and CD8+ cells in resting and activated states, in response to the mechanical pressure exerted by a three-dimensional in vitro system, able to recapitulate the rheological and stiffness properties of the tumor ECM.

Characterization of the Immune Cell Infiltration Landscape and a New Prognostic Score in Glioblastoma

“…For example, increased levels of tumor-infiltrating lymphocytes (TLSs) including CD4+ T cells and CD8+ T cells can improve the response and survival rate of immunotherapy [ 18 ]. It is worth noting that the excessive infiltration of extracellular matrix in tumor tissues will reduce the transport of TLS to the tumor [ 19 ]. This shows that the relationship between cells in TME is more critical than single-cell populations.…”

Cancer Associated Fibroblasts - An Impediment to Effective Anti-Cancer T Cell Immunity

“…Multiple studies have shown that CAF high tumours have low CD8 T cell infiltration, while Treg infiltration is actually increased in these tumours indicating that active stroma may affect cytotoxic T cells and Treg differently. A recent in vitro study modelling matrix stiffness in a 3D culture system, offers some insight into possible underlying mechanisms, and reports that the viability of CD4 + T cells exceeded that of CD8 + T cells in ECM with high rigidity, which could indicate that CD8 + T cells are more sensitive to mechanical pressure ( 57 ). Further studies are needed to understand the specific mechanisms by which CAFs selectively exclude CTL and promote Treg.…”

Biophysics involved in the process of tumor immune escape

“…Tumor stiffness reflects increased interstitial tissue pressure, solid stress, and elastic modulus ( Paszek et al., 2005 ). In terms of tumor immune escape, tumor stiffness is inextricably linked to this ( Chirivì et al., 2021 ; De Marco et al., 2022 ). In the tumor microenvironment, fibroblasts, which maintain tumor stiffness, can secrete factors such as CXCL12 to inhibit the movement of T cells toward the tumor.…”

“…TAZ appears to link the rigidity of tumor cells to the glucose metabolism function of dendritic cells. In general, it is very important to study the relationship between the hardness of tumor cells and matrix and immune cell metabolism and immune microenvironment remodeling ( Chirivì et al., 2021 ). A study by Rizzi’s team last year quantified the effect of tumor matrix stiffness on regulatory T lymphocytes in three ways ( Chirivì et al., 2021 ).…”

“…In general, it is very important to study the relationship between the hardness of tumor cells and matrix and immune cell metabolism and immune microenvironment remodeling ( Chirivì et al., 2021 ). A study by Rizzi’s team last year quantified the effect of tumor matrix stiffness on regulatory T lymphocytes in three ways ( Chirivì et al., 2021 ). First, when T cells are in a three-dimensional state, the pressure on the cell membrane is distributed throughout the cell, the cell suddenly becomes smaller, and the cell volume decreases significantly.…”