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Cancer Immunol Immunother. 2017 Dec;66(12):1563-1575. doi: 10.1007/s00262-017-2050-7. Epub 2017 Aug 10.

Mucosa-associated invariant T cells infiltrate hepatic metastases in patients with colorectal carcinoma but are rendered dysfunctional within and adjacent to tumor microenvironment.

Author information

1
Department of Microbiology and Immunology, Western University, 1151 Richmond Street, London, ON, N6A 5C1, Canada.
2
Department of Surgery, Western University, London, ON, N6A 4V2, Canada.
3
Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
4
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, 3010, Australia.
5
Division of Critical Care Medicine, Department of Medicine, Western University, London, ON, N6A 5A5, Canada.
6
Division of Transplantation, Department of Surgery, University of Rochester Medical Center, Rochester, NY, 14642, USA.
7
Department of Microbiology and Immunology, Western University, 1151 Richmond Street, London, ON, N6A 5C1, Canada. Mansour.Haeryfar@schulich.uwo.ca.
8
Division of Clinical Immunology and Allergy, Department of Medicine, Western University, London, ON, N6A 5A5, Canada. Mansour.Haeryfar@schulich.uwo.ca.
9
Centre for Human Immunology, Western University, London, ON, N6A 5C1, Canada. Mansour.Haeryfar@schulich.uwo.ca.
10
Lawson Health Research Institute, London, ON, N6C 2R5, Canada. Mansour.Haeryfar@schulich.uwo.ca.

Abstract

Mucosa-associated invariant T (MAIT) cells are innate-like T lymphocytes that are unusually abundant in the human liver, a common site of colorectal carcinoma (CRC) metastasis. However, whether they contribute to immune surveillance against colorectal liver metastasis (CRLM) is essentially unexplored. In addition, whether MAIT cell functions can be impacted by chemotherapy is unclear. These are important questions given MAIT cells' potent immunomodulatory and inflammatory properties. Herein, we examined the frequencies and functions of peripheral blood, healthy liver tissue, tumor-margin and tumor-infiltrating MAIT cells in 21 CRLM patients who received no chemotherapy, FOLFOX, or a combination of FOLFOX and Avastin before they underwent liver resection. We found that MAIT cells, defined as CD3ε+Vα7.2+CD161++ or CD3ε+MR1 tetramer+ cells, were present within both healthy and tumor-afflicted hepatic tissues. Paired and grouped analyses of samples revealed the physical proximity of MAIT cells to metastatic lesions to drastically influence their functional competence. Accordingly, unlike those residing in the healthy liver compartment, tumor-infiltrating MAIT cells failed to produce IFN-γ in response to a panel of TCR and cytokine receptor ligands, and tumor-margin MAIT cells were only partially active. Furthermore, chemotherapy did not account for intratumoral MAIT cell insufficiencies. Our findings demonstrate for the first time that CRLM-penetrating MAIT cells exhibit wide-ranging functional impairments, which are dictated by their physical location but not by preoperative chemotherapy. Therefore, we propose that MAIT cells may provide an attractive therapeutic target in CRC and that their ligands may be combined with chemotherapeutic agents to treat CRLM.

KEYWORDS:

Chemotherapy; Colon cancer; Immune surveillance; Liver metastasis; MAIT cells; Tumor-infiltrating lymphocytes

PMID:
28798979
DOI:
10.1007/s00262-017-2050-7
[Indexed for MEDLINE]

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