Altered T-Cell Balance in Lymphoid Organs of a Mouse Model of Colorectal Cancer

Tanner, Scott M.; Daft, Joseph G.; Hill, Stéphanie; Martin, Colin; Lorenz, Robin G.

doi:10.1369/0022155416672418

Cited by 13 publications

(10 citation statements)

References 27 publications

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“…Altered intestinal immune homeostasis was found in Apc mutant mice, together with the impaired control of inflammation by regulatory T lymphocytes (Tregs) (Akeus et al, 2014;Chae and Bothwell, 2015;Gounaris et al, 2009). However, whether Apc defects in T cells contribute to this loss of anti-inflammatory functions remains only vaguely explored (Tanner et al, 2016). Our data unveil the requirement for APC in T cell receptor-dependent nuclear factor of activated T cells (NFAT) activation.…”

Section: Introductionmentioning

confidence: 74%

Adenomatous Polyposis Coli Defines Treg Differentiation and Anti-inflammatory Function through Microtubule-Mediated NFAT Localization

et al. 2017

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Adenomatous polyposis coli (APC) is a polarity regulator and tumor suppressor associated with familial adenomatous polyposis and colorectal cancer development. Although extensively studied in epithelial transformation, the effect of APC on T lymphocyte activation remains poorly defined. We found that APC ensures T cell receptor-triggered activation through Nuclear Factor of Activated T cells (NFAT), since APC is necessary for NFAT's nuclear localization in a microtubule-dependent fashion and for NFAT-driven transcription leading to cytokine gene expression. Interestingly, NFAT forms clusters juxtaposed with microtubules. Ultimately, mouse Apc deficiency reduces the presence of NFAT in the nucleus of intestinal regulatory T cells (Tregs) and impairs Treg differentiation and the acquisition of a suppressive phenotype, which is characterized by the production of the anti-inflammatory cytokine IL-10. These findings suggest a dual role for APC mutations in colorectal cancer development, where mutations drive the initiation of epithelial neoplasms and also reduce Treg-mediated suppression of the detrimental inflammation that enhances cancer growth.

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Section: Introductionmentioning

confidence: 74%

Adenomatous Polyposis Coli Defines Treg Differentiation and Anti-inflammatory Function through Microtubule-Mediated NFAT Localization

et al. 2017

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“…In mouse Apc Min/+ model, an altered level of CD8 + cells was described, together with changes in IFN-γ and granzyme-B expression by these cells. Furthermore, in MLNs and PP of these mice, lower levels of IFN-γ + /IL-17 + double-positive CD4 + cells were observed [ 99 ].…”

Section: The Role Of Tumor Microenvironment (Tme) Cells In Crc-assmentioning

confidence: 99%

The Role of Tumor Microenvironment Cells in Colorectal Cancer (CRC) Cachexia

Kasprzak

2021

IJMS

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Cancer cachexia (CC) is a multifactorial syndrome in patients with advanced cancer characterized by weight loss via skeletal-muscle and adipose-tissue atrophy, catabolic activity, and systemic inflammation. CC is correlated with functional impairment, reduced therapeutic responsiveness, and poor prognosis, and is a major cause of death in cancer patients. In colorectal cancer (CRC), cachexia affects around 50–61% of patients, but remains overlooked, understudied, and uncured. The mechanisms driving CC are not fully understood but are related, at least in part, to the local and systemic immune response to the tumor. Accumulating evidence demonstrates a significant role of tumor microenvironment (TME) cells (e.g., macrophages, neutrophils, and fibroblasts) in both cancer progression and tumor-induced cachexia, through the production of multiple procachectic factors. The most important role in CRC-associated cachexia is played by pro-inflammatory cytokines, including the tumor necrosis factor α (TNFα), originally known as cachectin, Interleukin (IL)-1, IL-6, and certain chemokines (e.g., IL-8). Heterogeneous CRC cells themselves also produce numerous cytokines (including chemokines), as well as novel factors called “cachexokines”. The tumor microenvironment (TME) contributes to systemic inflammation and increased oxidative stress and fibrosis. This review summarizes the current knowledge on the role of TME cellular components in CRC-associated cachexia, as well as discusses the potential role of selected mediators secreted by colorectal cancer cells in cooperation with tumor-associated immune and non-immune cells of tumor microenvironment in inducing or potentiating cancer cachexia. This knowledge serves to aid the understanding of the mechanisms of this process, as well as prevent its consequences.

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“…The role of Apc in immune responses, in particular against tumors, is much less explored. However, altered intestinal immune homeostasis and control of inflammation by Tregs was reported in Apc mutant mice (25)(26)(27)(28). We have previously unveiled that Apc underpins various molecular mechanisms controlling CD4 T cell functions (29).…”

Section: Introductionmentioning

confidence: 99%

Adenomatous Polyposis Coli Modulates Actin and Microtubule Cytoskeleton at the Immunological Synapse to Tune CTL Functions

et al. 2020

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Adenomatous polyposis coli (Apc) is a cell polarity regulator and a tumor suppressor associated with familial adenomatous polyposis and colorectal cancer. Apc involvement in T lymphocyte functions and antitumor immunity remains poorly understood. Investigating Apc-depleted human CD8 T cells and CD8 T cells from Apc Min/+ mutant mice, we found that Apc regulates actin and microtubule cytoskeleton remodeling at the immunological synapse, controlling synapse morphology and stability and lytic granule dynamics, including targeting and fusion at the synapse. Ultimately, Apc tunes cytotoxic T cell activity, leading to tumor cell killing. Furthermore, Apc modulates early TCR signaling and nuclear translocation of the NFAT transcription factor with mild consequences on the expression of some differentiation markers. In contrast, no differences in the production of effector cytokines were observed. These results, together with our previous findings on Apc function in regulatory T cells, indicate that Apc mutations may cause a dual damage, first unbalancing epithelial cell differentiation and growth driving epithelial neoplasms and, second, impairing T cell-mediated antitumor immunity at several levels. ImmunoHorizons, 2020, 4: 363-381.

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Altered T-Cell Balance in Lymphoid Organs of a Mouse Model of Colorectal Cancer

Cited by 13 publications

References 27 publications

Adenomatous Polyposis Coli Defines Treg Differentiation and Anti-inflammatory Function through Microtubule-Mediated NFAT Localization

Adenomatous Polyposis Coli Defines Treg Differentiation and Anti-inflammatory Function through Microtubule-Mediated NFAT Localization

The Role of Tumor Microenvironment Cells in Colorectal Cancer (CRC) Cachexia

Adenomatous Polyposis Coli Modulates Actin and Microtubule Cytoskeleton at the Immunological Synapse to Tune CTL Functions

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