Lymphatic system regulation of anti-cancer immunity and metastasis

Pin-Ji Lei; Cameron Fraser; Dennis Jones; Jessalyn M Ubellacker; Timothy P Padera

doi:10.3389/fimmu.2024.1449291

Lymphatic system regulation of anti-cancer immunity and metastasis

Front Immunol. 2024 Aug 15:15:1449291. doi: 10.3389/fimmu.2024.1449291. eCollection 2024.

Authors

Pin-Ji Lei¹, Cameron Fraser², Dennis Jones³, Jessalyn M Ubellacker², Timothy P Padera¹

Affiliations

¹ Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
² Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, United States.
³ Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, United States.

Abstract

Cancer dissemination to lymph nodes (LN) is associated with a worse prognosis, increased incidence of distant metastases and reduced response to therapy. The LN microenvironment puts selective pressure on cancer cells, creating cells that can survive in LN as well as providing survival advantages for distant metastatic spread. Additionally, the presence of cancer cells leads to an immunosuppressive LN microenvironment, favoring the evasion of anti-cancer immune surveillance. However, recent studies have also characterized previously unrecognized roles for tumor-draining lymph nodes (TDLNs) in cancer immunotherapy response, including acting as a reservoir for pre-exhausted CD8+ T cells and stem-like CD8+ T cells. In this review, we will discuss the spread of cancer cells through the lymphatic system, the roles of TDLNs in metastasis and anti-cancer immune responses, and the therapeutic opportunities and challenges in targeting LN metastasis.

Keywords: cancer metastasis; immunotherapy; lymph node metastasis; lymphatic vessels; tumor-draining lymph node (TDLN).

Publication types

Review

MeSH terms

Animals
CD8-Positive T-Lymphocytes / immunology
Humans
Immunotherapy / methods
Lymph Nodes / immunology
Lymph Nodes / pathology
Lymphatic Metastasis* / immunology
Lymphatic System / immunology
Lymphatic System / pathology
Neoplasms* / immunology
Neoplasms* / pathology
Neoplasms* / therapy
Tumor Escape
Tumor Microenvironment* / immunology

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. TP is supported by grants from the NIH (R21AG072205, R21AI097745, R01CA214913, R01HL128168, R01CA284372, and R01CA284603), US Department of Defense Peer Reviewed Medical Research Program (HT94252410100), Koch Institute-Dana Farber/Harvard Cancer Center Bridge Grant and the Rullo Family MGH Research Scholar Award. JU is supported by NIH (R01CA282202) and grants from the Melanoma Research Foundation and Breast Cancer Research Alliance. DJ is supported by NIH (R01CA284133) and career development grants from the American Association for Cancer Research and Breast Cancer Research Foundation. CF is supported by T32DK128781 from the NIH.