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Cancer Immunology, Immunotherapy

, Volume 68, Issue 2, pp 175–188 | Cite as

The expression of MHC class II molecules on murine breast tumors delays T-cell exhaustion, expands the T-cell repertoire, and slows tumor growth

  • Tyler R. McCaw
  • Mei Li
  • Dmytro Starenki
  • Sara J. Cooper
  • Mingyong Liu
  • Selene Meza-Perez
  • Rebecca C. Arend
  • Donald J. Buchsbaum
  • Andres Forero
  • Troy D. RandallEmail author
Original Article

Abstract

The expression of MHC class II molecules (MHCII) on tumor cells correlates with survival and responsiveness to immunotherapy. However, the mechanisms underlying these observations are poorly defined. Using a murine breast tumor line, we showed that MHCII-expressing tumors grew more slowly than controls and recruited more functional CD4+ and CD8+ T cells. In addition, MHCII-expressing tumors contained more TCR clonotypes expanded to a larger degree than control tumors. Functional CD8+ T cells in tumors depended on CD4+ T cells. However, both CD4+ and CD8+ T cells eventually became exhausted, even in MHCII-expressing tumors. Treatment with anti-CTLA4, but not anti-PD-1 or anti-TIM-3, promoted complete eradication of MHCII-expressing tumors. These results suggest tumor cell expression of MHCII facilitates the local activation of CD4+ T cells, indirectly helps the activation and expansion of CD8+ T cells, and, in combination with the appropriate checkpoint inhibitor, promotes tumor regression.

Keywords

Breast cancer MHC class II T-cell exhaustion TCR repertoire 

Abbreviations

gp70

Glycoprotein 70

GZB

Granzyme B

hCIITA

Human class II transcriptional activator

MHCII

MHC class II

MuLV

Murine leukemia virus

Notes

Acknowledgements

The authors would like to thank Uma Mudunuru and Scott Simpler for animal husbandry, Eddy Yang and Debbie Della Manna of the NanoString Laboratory and Enid Keyser of the Comprehensive Flow Cytometry Core for lending respective expertise. The TS/A murine mammary adenocarcinoma cell line was provided by Roberto S. Accolla, Department of Clinical and Biological Sciences, University of Insubria, Italy.

Author contributions

TRM designed, performed, and interpreted experiments, and wrote the manuscript. ML designed, performed, and interpreted experiments. DS performed TCR repertoire sequencing and analysis. SJC performed TCR repertoire sequencing and analysis. ML designed, performed, and interpreted experiments. SM-P designed, performed, and interpreted experiments. RCA designed and interpreted experiments and edited the manuscript. DJB designed and interpreted experiments and edited the manuscript. AF designed and interpreted experiments and edited the manuscript. TDR designed and interpreted experiments and edited the manuscript.

Funding

This work was supported by the University of Alabama at Birmingham Comprehensive Cancer Center (P30 CA013148), National Institutes of Health Grant CA216234, and by the Breast Cancer Research Foundation of Alabama.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures involving animals were performed in accordance with the guidelines of the National Research Council (United States) Committee for the Update of the Guide for the Care and Use of Laboratory Animals and were approved by the University of Alabama at Birmingham Institutional Animal Care and Use Committee (IACUC) in protocol 09854.

Research involving human participants and animals

BALB/c mice were purchased from Charles River Laboratories International, Inc. BALB/c.scid mice (CBySmn.CB17-PrkdcscidIJ) were purchased from The Jackson Laboratory.

Cell line authentication

TS/A cells were obtained at passage 22 and passaged 2 times prior to freezing archival samples. TS/A cells were authenticated by assessing MHC haplotype via flow cytometry and by detection of antigens from murine leukemia virus. Transfected and control TS/A cells were also confirmed by gene expression of MHCII pathway gene products using nanostring assay and Western blot. Both cell lines tested negative for mycoplasma (and 13 other mouse pathogens) via PCR performed by Charles River Research Animal Diagnostic Services on June 2015.

Supplementary material

262_2018_2262_MOESM1_ESM.pdf (2.6 mb)
Supplementary material 1 (PDF 2627 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Clinical Immunology and Rheumatology, Department of MedicineUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.Department of Radiation OncologyUniversity of Alabama at BirminghamBirminghamUSA
  3. 3.HudsonAlpha Institute for BiotechnologyHuntsvilleUSA
  4. 4.Department of Obstetrics and GynecologyUniversity of Alabama at BirminghamBirminghamUSA
  5. 5.Division of Hematology and Oncology, Department of MedicineUniversity of Alabama at BirminghamBirminghamUSA

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