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Tumor-draining lymph nodes are survival niches that support T cell priming against lymphatic transported tumor antigen and effects of immune checkpoint blockade in TNBC

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Abstract

Triple negative breast cancer (TNBC) is a significant clinical problem to which immunotherapeutic strategies have been applied with limited success. Using the syngeneic E0771 TNBC mouse model, this work explores the potential for antitumor CD8+ T cell immunity to be primed extratumorally in lymphoid tissues and therapeutically leveraged. CD8+ T cell viability and responses within the tumor microenvironment (TME) were found to be severely impaired, effects coincident with local immunosuppression that is recapitulated in lymphoid tissues in late stage disease. Prior to onset of a locally suppressed immune microenvironment, however, CD8+ T cell priming within lymph nodes (LN) that depended on tumor lymphatic drainage remained intact. These results demonstrate tumor-draining LNs (TdLN) to be lymphoid tissue niches that support the survival and antigenic priming of CD8+ T lymphocytes against lymph-draining antigen. The therapeutic effects of and CD8+ T cells response to immune checkpoint blockade were furthermore improved when directed to LNs within the tumor-draining lymphatic basin. Therefore, TdLNs represent a unique potential tumor immunity reservoir in TNBC for which strategies may be developed to improve the effects of ICB immunotherapy.

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Acknowledgements

We thank Paul Archer for technical assistance.

Funding

This work was supported by a Komen Foundation Career Catalyst Grant CCR15330478, US National Institutes of Health Grants R01CA207619 (SNT), U01CA214354 (SNT), T32GM008433 (MJO), S10OD016264, and Georgia CORE/It’s the Journey. MPM was a National Science Foundation Graduate Research Fellow.

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Authors and Affiliations

  1. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, IBB 2310, 315 Ferst Drive NW, Atlanta, GA, 30332, USA

    Meghan J. O’Melia & Susan N. Thomas

  2. Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA

    Margaret P. Manspeaker & Susan N. Thomas

  3. School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA

    Margaret P. Manspeaker

  4. George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA

    Susan N. Thomas

  5. Winship Cancer Institute, Emory University, Atlanta, GA, 30332, USA

    Susan N. Thomas

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  1. Meghan J. O’Melia
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MJO and SNT designed all experiments and wrote manuscript. MJO carried out all experiments and analyzed all data. MPM assisted in carrying out therapeutic experiments. All authors reviewed and approved the manuscript for submission.

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Correspondence to Susan N. Thomas.

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O’Melia, M.J., Manspeaker, M.P. & Thomas, S.N. Tumor-draining lymph nodes are survival niches that support T cell priming against lymphatic transported tumor antigen and effects of immune checkpoint blockade in TNBC. Cancer Immunol Immunother 70, 2179–2195 (2021). https://doi.org/10.1007/s00262-020-02792-5

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