Abstract
The intestinal immune system has the difficult task of protecting a large environmentally exposed single layer of epithelium from pathogens without allowing inappropriate inflammatory responses. Unmitigated inflammation drives multiple pathologies, including the development of colorectal cancer. CD4+T cells mediate both the suppression and promotion of intestinal inflammation. They comprise an array of phenotypically and functionally distinct subsets tailored to a specific inflammatory context. This diversity of form and function is relevant to a broad array of pathologic and physiologic processes. The heterogeneity underlying both effector and regulatory T helper cell responses to colorectal cancer, and its impact on disease progression, is reviewed herein. Importantly, T cell responses are dynamic; they exhibit both quantitative and qualitative changes as the inflammatory context shifts. Recent evidence outlines the role of CD4+T cells in colorectal cancer responses and suggests possible mechanisms driving qualitative alterations in anti-cancer immune responses. The heterogeneity of T cells in colorectal cancer, as well as the manner and mechanism by which they change, offer an abundance of opportunities for more specific, and likely effective, interventional strategies.
Highlights
Despite being exposed to billions of microbes and their products, the basal tone of a healthy gut immune system is overtly tolerogenic
Chronic inflammation carries additional risk: it is a key factor in the development and progression of colorectal carcinoma (CRC) [1]
The capacity to switch between tolerogenic and inflammatory states is one of the most critical aspects of gut immunity. This delicate balance is orchestrated by counteracting classes of CD4+T cells
Summary
Despite being exposed to billions of microbes and their products, the basal tone of a healthy gut immune system is overtly tolerogenic. Some eTreg cells demonstrate compromised suppressor function and promote anti-tumor immunity, including in colorectal carcinoma (CRC) [72] This phenomenon, discussed in greater detail below, appears dependent on expression of canonical effector transcription factors. Caution is warranted as some studies indicate disruption of Th17 and Th22 cell function can promote tumor development and progression [171] The cause of these disparate outcomes is not fully understood, but may relate to the specific mechanism of CRC pathogenesis and the role of T cells in promoting appropriate versus chronic, dysregulated inflammatory responses. Very little is known about the signaling and transcriptional events that guide this transition Both IL-12 and TGF-b are elevated in CRC tissue infiltrated by FOXP3-low eTregs, suggesting these factors could promote acquisition of a pro-inflammatory phenotype. The potential therapeutic utility is apparent but, as before, our ability to exploit this potential is hampered by an abridged appreciation of biology
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