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Cancer Immunology, Immunotherapy

, Volume 66, Issue 12, pp 1563–1575 | Cite as

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

  • Christopher R. Shaler
  • Mauro E. Tun-Abraham
  • Anton I. Skaro
  • Khashayarsha Khazaie
  • Alexandra J. Corbett
  • Tina Mele
  • Roberto Hernandez-Alejandro
  • S. M. Mansour Haeryfar
Original Article

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

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

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

Notes

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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

262_2017_2050_MOESM1_ESM.pdf (640 kb)
Supplementary material 1 (PDF 639 kb)

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Christopher R. Shaler
    • 1
  • Mauro E. Tun-Abraham
    • 2
  • Anton I. Skaro
    • 2
  • Khashayarsha Khazaie
    • 3
  • Alexandra J. Corbett
    • 4
  • Tina Mele
    • 2
    • 5
  • Roberto Hernandez-Alejandro
    • 2
    • 6
  • S. M. Mansour Haeryfar
    • 1
    • 7
    • 8
    • 9
  1. 1.Department of Microbiology and ImmunologyWestern UniversityLondonCanada
  2. 2.Department of SurgeryWestern UniversityLondonCanada
  3. 3.Department of ImmunologyMayo Clinic College of MedicineRochesterUSA
  4. 4.Department of Microbiology and Immunology, Peter Doherty Institute for Infection and ImmunityUniversity of MelbourneParkvilleAustralia
  5. 5.Division of Critical Care Medicine, Department of MedicineWestern UniversityLondonCanada
  6. 6.Division of Transplantation, Department of SurgeryUniversity of Rochester Medical CenterRochesterUSA
  7. 7.Division of Clinical Immunology and Allergy, Department of MedicineWestern UniversityLondonCanada
  8. 8.Centre for Human Immunology, Western UniversityLondonCanada
  9. 9.Lawson Health Research InstituteLondonCanada

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