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

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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.

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Abbreviations

ABCB1:

ATP-binding cassette subfamily B member 1

ASA:

American Society of Anesthesiologists

CRC:

Colorectal carcinoma

CRLM:

Colorectal liver metastasis

ECOG:

Eastern cooperative oncology group

FOLFOX:

Leucovorin calcium (folinic acid)/5-fluorouracil/oxaliplatin

6-FP:

6-formylpterin

GZM B:

Granzyme B

HMNCs:

Hepatic [non-parenchymal] mononuclear cells

MAIT:

Mucosa-associated invariant T [cell]

MDR1:

Multi-drug resistance protein 1

MNCs:

[non-parenchymal] mononuclear cells

MR1:

MHC-related protein 1

NKG2D:

Natural-killer group 2, member D

NKT:

Natural killer T [cell]

5-OP-RU:

5-(2-oxopropylideneamino)-6-D-ribitylaminouracil

rIL:

Recombinant [human] interleukin

SEB:

Staphylococcal enterotoxin B

TH1:

T helper 1

TH17:

T helper 17

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Acknowledgements

This work was funded by a Canadian Institutes of Health Research (CIHR) operating Grant (MOP-130465) to S.M. Mansour Haeryfar and by a Dean’s Research Initiative Award from Schulich School of Medicine and Dentistry, Western University, to Roberto Hernandez-Alejandro and S.M. Mansour Haeryfar. Khashayarsha Khazaie is supported by grant R01CA160436 from NIH, and Christopher R. Shaler is a CIHR postdoctoral fellowship recipient. We thank members of the Haeryfar laboratory for helpful discussions, Delfina Mazzuca for production and purification of staphylococcal enterotoxin B, and Katie Bain for technical assistance with preparation of Klebsiella lysate.

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Author notes

  1. Christopher R. Shaler, Mauro E. Tun-Abraham contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology and Immunology, Western University, 1151 Richmond Street, London, ON, N6A 5C1, Canada

    Christopher R. Shaler & S. M. Mansour Haeryfar

  2. Department of Surgery, Western University, London, ON, N6A 4V2, Canada

    Mauro E. Tun-Abraham, Anton I. Skaro, Tina Mele & Roberto Hernandez-Alejandro

  3. Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

    Khashayarsha Khazaie

  4. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, 3010, Australia

    Alexandra J. Corbett

  5. Division of Critical Care Medicine, Department of Medicine, Western University, London, ON, N6A 5A5, Canada

    Tina Mele

  6. Division of Transplantation, Department of Surgery, University of Rochester Medical Center, Rochester, NY, 14642, USA

    Roberto Hernandez-Alejandro

  7. Division of Clinical Immunology and Allergy, Department of Medicine, Western University, London, ON, N6A 5A5, Canada

    S. M. Mansour Haeryfar

  8. Centre for Human Immunology, Western University, London, ON, N6A 5C1, Canada

    S. M. Mansour Haeryfar

  9. Lawson Health Research Institute, London, ON, N6C 2R5, Canada

    S. M. Mansour Haeryfar

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  1. Christopher R. Shaler
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Shaler, C.R., Tun-Abraham, M.E., Skaro, A.I. et al. Mucosa-associated invariant T cells infiltrate hepatic metastases in patients with colorectal carcinoma but are rendered dysfunctional within and adjacent to tumor microenvironment. Cancer Immunol Immunother 66, 1563–1575 (2017). https://doi.org/10.1007/s00262-017-2050-7

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