Colorectal Cancer-Infiltrating Regulatory T Cells: Functional Heterogeneity, Metabolic Adaptation, and Therapeutic Targeting

Abstract

Colorectal cancer (CRC) is a heterogeneous disease with one of the highest rates of incidence and mortality among cancers worldwide. Understanding the CRC tumor microenvironment (TME) is essential to improve diagnosis and treatment. Within the CRC TME, tumor-infiltrating lymphocytes (TILs) consist of a heterogeneous mixture of adaptive immune cells composed of mainly anti-tumor effector T cells (CD4+ and CD8+ subpopulations), and suppressive regulatory CD4+ T (Treg) cells. The balance between these two populations is critical in anti-tumor immunity. In general, while tumor antigen-specific T cell responses are observed, tumor clearance frequently does not occur. Treg cells are considered to play an important role in tumor immune escape by hampering effective anti-tumor immune responses. Therefore, CRC-tumors with increased numbers of Treg cells have been associated with promoting tumor development, immunotherapy failure, and a poorer prognosis. Enrichment of Treg cells in CRC can have multiple causes including their differentiation, recruitment, and preferential transcriptional and metabolic adaptation to the TME. Targeting tumor-associated Treg cell may be an effective addition to current immunotherapy approaches. Strategies for depleting Treg cells, such as low-dose cyclophosphamide treatment, or targeting one or more checkpoint receptors such as CTLA-4 with PD-1 with monoclonal antibodies, have been explored. These have resulted in activation of anti-tumor immune responses in CRC-patients. Overall, it seems likely that CRC-associated Treg cells play an important role in determining the success of such therapeutic approaches. Here, we review our understanding of the role of Treg cells in CRC, the possible mechanisms that support their homeostasis in the tumor microenvironment, and current approaches for manipulating Treg cells function in cancer.

Inactivation of interleukin-30 in colon cancer stem cells via CRISPR/Cas9 genome editing inhibits their oncogenicity and improves host survival

“…Immune exhaustion with high levels of expression of PD-L1 and LAG-3 correlates with a shorter OS in CRC patients, 44 and accumulation of Tregs has been associated with CRC progression and metastasis, immunotherapy failure and a poorer prognosis. 45 …”

“…Immune exhaustion with high levels of expression of PD-L1 and LAG-3 correlates with a shorter OS in CRC patients, 44 and accumulation of Tregs has been associated with CRC progression and metastasis, immunotherapy failure and a poorer prognosis. 45 So far, the role of IL30 in colorectal tumorigenesis has never been explored. Here, we provide evidence that IL30 expressed, as membrane-anchored cytokine, in both stem and non-stem CRC cells, regulates their viability, immunophenotype and tumor progression programs.…”

TGFβ and the Tumor Microenvironment in Colorectal Cancer

“…While Th17 and Th22 cells directly promote tumor progression through the release of tumor-promoting cytokines such as IL-17A or IL-17, Tregs suppress the anti-tumor effector response of Th1 cells and cytotoxic CD8 T cells. However, data shedding light on the role of individual Treg subtypes in CRC revealed that this is not always the case (for review, see [ 55 ]). For instance, CD4 + CD25 + Tregs have been shown to suppress inflammation-associated CRC development through the release of IL-10 [ 56 ], and induce CRC regression in the Apcmin/+ mouse model of CRC by regulating the homeostasis of epithelial cells [ 57 ].…”

A Treg‐related riskscore model may improve the prognosis evaluation of colorectal cancer

“…The components of TIICs in the tumor microenvironment (TME) even influence the drug sensitivity and prognosis of cancer 5 . Regulatory T cells (Tregs) are an important subtype of TIICs with two‐sided roles in the context of CRC 6 . On the one hand, an abundance of Tregs can inhibit the activity of effector T cells, particularly cytotoxic T cells, creating a sanctuary that shields cancer cells from immune recognition and elimination 7 .…”

“…5 Regulatory T cells (Tregs) are an important subtype of TIICs with two-sided roles in the context of CRC. 6 On the one hand, an abundance of Tregs can inhibit the activity of effector T cells, particularly cytotoxic T cells, creating a sanctuary that shields cancer cells from immune recognition and elimination. 7 Through the secretion of pro-angiogenic factors, Tregs facilitate the formation of new blood vessels, ensuring the nutrient supply for sustained tumor development.…”