Cancer-Associated Fibroblast Mediated Inhibition of CD8+ Cytotoxic T Cell Accumulation in Tumours: Mechanisms and Therapeutic Opportunities

Abstract

The tumour microenvironment (TME) is the complex environment in which various non-cancerous stromal cell populations co-exist, co-evolve and interact with tumour cells, having a profound impact on the progression of solid tumours. The TME is comprised of various extracellular matrix (ECM) proteins in addition to a variety of immune and stromal cells. These include tumour-associated macrophages, regulatory T cells (Tregs), myeloid-derived suppressor cells, as well as endothelial cells, pericytes and cancer-associated fibroblasts (CAFs). CAFs are the most abundant stromal cell population in many tumours and support cancer progression, metastasis and resistance to therapies through bidirectional signalling with both tumour cells and other cells within the TME. More recently, CAFs have been shown to also affect the anti-tumour immune response through direct and indirect interactions with immune cells. In this review, we specifically focus on the interactions between CAFs and cytotoxic CD8+ T cells, and on how these interactions affect T cell recruitment, infiltration and function in the tumour. We additionally provide insight into the therapeutic implications of targeting these interactions, particularly in the context of cancer immunotherapy.

RETRACTED: Tumor Microenvironment in Oral Cancer Following Neoadjuvant Pembrolizumab: Preliminary Analysis of the Histopathologic Findings

“…CAFs, the major component of TME, have been shown to play a key-role in creating the immune-suppression milieu [5][6][7][8]. CAFs have the ability to inhibit T cell proliferation and differentiation and to upregulate expression of PD-L1 on the tumor cells, thus leading to T cell exhaustion, driving polarization of macrophages toward a pro-tumorigenic phenotype (CD163 + ), and encouraging the influx of T regulatory cells (FOXP3 + ) and other myeloid-derived suppressor cells.…”

“…The tumor microenvironment (TME) is the complex milieu of non-malignant cells and extra-cellular matrix components that surrounds solid tumors and it is the reciprocity of TMEtumor relations that ultimately defines the malignant behavior [5]. The TME is regarded as a major mediator of immune suppression in many solid cancers [6][7][8].…”

Hypoxia increases melanoma-associated fibroblasts immunosuppressive potential and inhibitory effect on T cell-mediated cytotoxicity

“…As previously mentioned, several studies have pointed out that CAFs can regulate T cell activity and function in the TME by the secretion of several factors, 20 including TGF-β, ARG or IDO. Thus, to validate the physiological relevance of our data pointing out improved immunosuppressive capabilities of hypoxic CAFs, we used T1 melanoma tumor cells and the autologous LT12 CTL clone in order to test the differential effect of normoxic versus hypoxic CAF CMs on T cell cytotoxic activity.…”

“…10,11 Importantly, CAFs have also emerged as important regulators of the anti-tumor immune response and several studies have shown that CAFs exhibit a particular immunomodulatory proteome and secretome that can potentially regulate both innate and adaptive anti-tumor immune responses. [12][13][14] For example, CAFs can increase the recruitment and differentiation of myeloid-derived suppressive cells (MDSC), 15 regulatory T cells (Tregs) 16 or type 2 tumorassociated macrophages (TAM) within the TME, 17,18 can affect dendritic cell (DC) maturation and antigen presentation functions 19 or can alter proliferation, survival and cytolytic functions of cytotoxic T cells (CTL) 20 and natural killer (NK) cells. [21][22][23] Another component of the TME is hypoxia.…”

Targeting Fibrosis: The Bridge That Connects Pancreatitis and Pancreatic Cancer

“…ApCAFs present antigens to T cells and affect T cell immunity [ 110 ]. ApCAFs can induce CD4+ Tregs differentiation through antigen-dependent T cell antigen receptor (TCR) ligation, reduce the anti-tumor immune response by changing the ratio of CD8+ T cells to Tregs and prevent PC cells from being monitored by immune cells [ 110 , 112 , 113 ]. According to the latest research, all three of these CAFs can transform into each other, which emphasizes the dynamic process of TME [ 114 , 115 ].…”