Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies

Abstract

T cell dysfunction in solid tumors results from multiple mechanisms. Altered signaling pathways in tumor cells help produce a suppressive tumor microenvironment enriched for inhibitory cells, posing a major obstacle for cancer immunity. Metabolic constraints to cell function and survival shape tumor progression and immune cell function. In the face of persistent antigen, chronic T cell receptor signaling drives T lymphocytes to a functionally exhausted state. Here we discuss how the tumor and its microenvironment influences T cell trafficking and function with a focus on melanoma, pancreatic and ovarian cancer, and discuss how scientific advances may help overcome these hurdles.

Role of LFA-1 and ICAM-1 in Cancer

“…Tumor infiltrating lymphocytes need LFA-1 to adhere to target cells Cancer cells can escape from the immune response by changing the tumor microenvironment into an immune-suppressive one [13]. Indeed, the presence of an immune-suppressive Leukocytes in the tumor stroma can play a positive or negative role in tumor growth…”

“…Tumor infiltrating lymphocytes need LFA-1 to adhere to target cells Cancer cells can escape from the immune response by changing the tumor microenvironment into an immune-suppressive one [13]. Indeed, the presence of an immune-suppressive regulatory T cell infiltrate within a tumor correlates with reduced survival [14], but not if the nature of the T cell infiltrate is inflammatory [15].…”

“…LFA-1 is an essential initiator of the immunological synapse that forms between the cytotoxic T or NK cell and the cancer cell, and mediates the firm adhesion to the target cell and the polarization of cytotoxic granules towards the target [7] [10] [11]. There is a positive correlation between the maturation state of NK cells, their cytotoxic potential and the activation level of LFA-1 [12].Tumor infiltrating lymphocytes need LFA-1 to adhere to target cells Cancer cells can escape from the immune response by changing the tumor microenvironment into an immune-suppressive one [13]. Indeed, the presence of an immune-suppressive Leukocytes in the tumor stroma can play a positive or negative role in tumor growth…”

Mesenchymal traits at the convergence of tumor-intrinsic and -extrinsic mechanisms of resistance to immune checkpoint blockers

“…stiffened tissue with high matrix fiber mass and dense collagen network) [113] or the low expression of specific chemokines involved in T-cell recruitment [13,31,114]. Often, the hindrance of lymphocyte infiltration and trafficking is accompanied by the recruitment of suppressive cells and may also be ascribed to abnormal neovasculature derived from VEGF tumor overexpression [21,115,116] and down-modulation by tumor cells of adhesion and chemotactic signals on tumor endothelium, all features found in signatures related to ICB resistance [21,30,117].…”

“…Targeting the major ICBs, such as cytotoxic T-lymphocyte antigen (CTLA)-4, programmed cell death (PD)-1 and programmed cell death ligand (PD-L)1, is revolutionizing cancer therapy [28,29]. Notwithstanding the unprecedented durable response rates observed, the benefit has been limited to a minority of patients and primary and acquired resistance emerge, based on mechanisms relying on the dynamic reciprocity modulated by TME, which interferes with antitumor immunity and in particular T-cell activity [30,31]. In resting T-cells, CTLA-4 resides intracellularly.…”