Gut microbiota modulate T cell trafficking into human colorectal cancer

Cremonesi, Eleonora; Governa, Valeria; Garzon, Jesus F. Glaus; Mele, Valentina; Amicarella, Francesca; Muraro, Manuele Giuseppe; Trella, Emanuele; Galati-Fournier, Virginie; Oertli, Daniel; Däster, Silvio; Droeser, Raoul A.; Weixler, Benjamin; Bolli, Martin; Rosso, Raffaele; Nitsche, Ulrich; Khanna, Nina; Egli, Adrian; Keck, Simone; Slotta‐Huspenina, Julia; Terracciano, Luigi; Zajac, Paul; Spagnoli, Giulio C.; Eppenberger‐Castori, Serenella; Janssen, Klaus–Peter; Borsig, Lubor; Iezzi, Giovanna

doi:10.1136/gutjnl-2016-313498

Cited by 221 publications

(155 citation statements)

References 28 publications

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“…In their study on PDAC microbiome, Pushalkar et al (59) found that, although endogenous bacterial dysbiosis triggered immune suppression, Treg differentiation did not differ in PDAC-bearing and WT mice. Similar results were observed in another study (117), where the number of Foxp3 + T cells isolated from the spleen was not different between PBS-and Bifidobacteriumtreated mice, but genes targeted to certain metabolic pathways of Tregs, such as cellular macromolecules and organic substances, were expressed differentially. It remains to be verified whether the involvement of Tregs is the main cause of differential response to immunotherapy.…”

Section: Decreasing Peripherally Derived Tregssupporting

confidence: 88%

Gut Microbiome as a Potential Factor for Modulating Resistance to Cancer Immunotherapy

et al. 2020

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Gut microbiota refers to the diverse community of more than 100 trillion microorganisms residing in our intestines. It is now known that any shift in the composition of gut microbiota from that present during the healthy state in an individual is associated with predisposition to multiple pathological conditions, such as diabetes, autoimmunity, and even cancer. Currently, therapies targeting programmed cell death protein 1/programmed cell death 1 ligand 1 or cytotoxic T-lymphocyte antigen-4 are the focus of cancer immunotherapy and are widely applied in clinical treatment of various tumors. Owing to relatively low overall response rate, however, it has been an ongoing research endeavor to identify the mechanisms or factors for improving the therapeutic efficacy of these immunotherapies. Other than causing mutations that affect gene expression, some gut bacteria may also activate or repress the host's response to immune checkpoint inhibitors. In this review, we have described recent advancements made in understanding the regulatory relationship between gut microbiome and cancer immunotherapy. We have also summarized the potential molecular mechanisms behind this interaction, which can serve as a basis for utilizing different kinds of gut bacteria as promising tools for reversing immunotherapy resistance in cancer.

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Section: Decreasing Peripherally Derived Tregssupporting

confidence: 88%

Gut Microbiome as a Potential Factor for Modulating Resistance to Cancer Immunotherapy

et al. 2020

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“…By binding to corresponding CKRs on the target cell membrane, chemokines can induce the targeted migration of target cells (20). The interaction between chemokines released in an abnormal cancer microenvironment and CKRs on the surface of CIK cells is an important factor that affects the tumor-targeted migration ability of CIK cells (21). The concordance between these two variables directly affects the treatment effects of CIK cells (22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

Application of the chemokine‑chemokine receptor axis increases the tumor‑targeted migration ability of cytokine‑induced killer cells in patients with colorectal cancer

Zou

Liang

et al. 2020

Oncol Lett

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Cytokine-induced killer (CIK) cells are a group of heterogeneous immune cells which can be isolated from human peripheral blood mononuclear cells and have demonstrated therapeutic benefit both in hematologic malignancies and solid tumors, including colorectal cancer. However, poor tumor-targeted migration has limited the clinical efficacy of CIK cell treatment. The chemokine-chemokine receptor (CK-CKR) axis serves a role in the tumor-directed trafficking capacity of immune cells. Investigating the relationship between CKR profiles on the surface of CIK cells and chemokine expression levels in the tumor microenvironment may improve CIK cell therapy. In the present study, the spectrum of chemokine expression levels in tumor tissues from patients with colorectal cancer (CRC) and CKR expression profiles in CIK cells obtained from the same individuals with CRC were investigated. The results showed that chemokine expression levels in tumor tissues exhibited variability and cell line heterogeneity. However, the expression levels of a number of chemokines were similar in different CRC donors and cell lines. Expression levels of CXCLL10, CXCL11 and CCL3 were significantly higher in most tumor tissues compared with adjacent normal tissues and highly expressed in most CRC cell lines. In accordance with chemokine expression levels, CKR profiles on the surface of CIK cells also showed donor-to-donor variability. However, concordant expression profiles of CKRs were identified in different patients with CRC. CXCR3 and CXCR4 were highly expressed on the surface of CIK cells through the culture process. Importantly, the expression levels of all CKRs, especially CCR4, CXCR4 and CXCR3, were notably decreased during the course of CIK cell expansion. The changing trend of CKR profiles were not correlated with the chemokine expression profiles in CRC tissues (CCL3, CXCL12 and CXCL10/CXCL11 were highly expressed in CRC tissue). Re-stimulating CIK cells using chemokines (CCL21 and CXCL11) at the proper time point increased corresponding CKR expression levels on the surface of CIK cells and enhance tumor-targeted trafficking in vitro. These results demonstrated that modification of the CK-CKR axis using exogenous recombinant chemokines at the proper time point enhanced CIK cell trafficking ability and improved CIK antitumor effects.

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“…Further, we have shown recently that specific microbiota, as likely initiators of TLR/MyD88-signalling, are associated with T-cell populations and prognosis in human colorectal cancer. 24 Thus, blocking MyD88 in a therapeutic context might engage anti-tumoral effects of the adaptive immunity. Previously, TLR signaling was reported to induce EMT and tumor malignancy in hepatocellular cancer cell lines, however not for colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

Cell-type specific MyD88 signaling is required for intestinal tumor initiation and progression to malignancy

Holtorf

Conrad²,

Holzmann³

et al. 2018

OncoImmunology

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The signal adapter MyD88, an essential component of Toll-like receptor (TLR) signaling, is important for gut-microbiome interactions. However, its contribution to cancer and its cell-type specific functions are controversially discussed. Therefore, we generated new tissue-specific mouse models and analyzed the clinical importance in human colorectal cancer. A gene-trap was inserted into the murine Myd88 gene (Myd88LSL), yielding MyD88-deficient background with Cre-mediated re-expression in myeloid (MYEL) or intestinal epithelial cells (IECs). These lines were bred with the Apc1638N model that develops invasive adenocarcinoma and analyzed at 12 months. Further, two patient collectives of colorectal cancer (n = 61, and n = 633) were analyzed for expression of Myd88 and TLRs. MyD88 expression was significantly increased in carcinomas, and increased intratumoral levels of MyD88 and TLR pathway components were associated with significantly shorter disease-free (P = .011), and overall survival (P < .0001). In accordance, fully MyD88-deficient mice showed highly significantly decreased tumor incidence, tumor numbers, increased survival, and, importantly, fully lacked malignant lesions. Thus, MyD88 is essential for tumorigenesis and especially progression to malignancy. Tissue-specific re-expression of MyD88 highly significantly increased tumor initiation by differing mechanisms. In intestinal epithelia, MyD88 enhanced epithelial turnover, whereas in myeloid cells, it led to increased production of tumor- and stemness-enhancing cytokines, significantly associated with altered expression of adaptive immune genes. However, neither re-expression of MyD88 in IECs or myeloid cells was sufficient for malignant progression to carcinoma. Thus, MyD88 crucially contributes to colorectal cancer initiation and progression with non-redundant and cell-type specific functions, constituting an attractive therapeutic target.

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Gut microbiota modulate T cell trafficking into human colorectal cancer

Abstract: Gut microbiota stimulate chemokine production by CRC cells, thus favouring recruitment of beneficial T cells into tumour tissues.

Cited by 221 publications

References 28 publications

Gut Microbiome as a Potential Factor for Modulating Resistance to Cancer Immunotherapy

Gut Microbiome as a Potential Factor for Modulating Resistance to Cancer Immunotherapy

Application of the chemokine‑chemokine receptor axis increases the tumor‑targeted migration ability of cytokine‑induced killer cells in patients with colorectal cancer

Cell-type specific MyD88 signaling is required for intestinal tumor initiation and progression to malignancy

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