Tumor Lymphatic Function Regulates Tumor Inflammatory and Immunosuppressive Microenvironments.

TitleTumor Lymphatic Function Regulates Tumor Inflammatory and Immunosuppressive Microenvironments.
Publication TypeJournal Article
Year of Publication2019
AuthorsKataru RP, Ly CL, Shin J, Park HJu, Baik JEun, Rehal S, Ortega S, Lyden D, Mehrara BJ
JournalCancer Immunol Res
Volume7
Issue8
Pagination1345-1358
Date Published2019 Aug
ISSN2326-6074
KeywordsAnimals, Biomarkers, Tumor, Breast Neoplasms, Cytokines, Disease Models, Animal, Disease Progression, Edema, Female, Immunomodulation, Inflammation, Lymphatic System, Lymphatic Vessels, Lymphocytes, Tumor-Infiltrating, Male, Melanoma, Experimental, Mice, Neoplasms, Tumor Microenvironment
Abstract

Proliferation of aberrant, dysfunctional lymphatic vessels around solid tumors is a common histologic finding. Studies have shown that abnormalities in lymphatic function result in accumulation of inflammatory cells with an immunosuppressive profile. We tested the hypothesis that dysfunctional lymphatic vessels surrounding solid tumors regulate changes in the tumor microenvironment and tumor-specific immune responses. Using subcutaneously implanted mouse melanoma and breast cancer tumors in a lymphatic endothelial cell-specific diphtheria toxin receptor transgenic mouse, we found that local ablation of lymphatic vessels increased peritumoral edema, as compared with controls. Comparative analysis of the peritumoral fluid demonstrated increases in the number of macrophages, CD4+ inflammatory cells, F4/80+/Gr-1+ (myeloid-derived suppressor cells), CD4+/Foxp3+ (Tregs) immunosuppressive cells, and expression of inflammatory cytokines such as TNFα, IFNγ, and IL1β following lymphatic ablation. Tumors grown in lymphatic ablated mice exhibited reduced intratumoral accumulation of cytotoxic T cells and increased tumor PD-L1 expression, causing rapid tumor growth, compared with tumors grown in nonlymphatic-ablated mice. Our study suggests that lymphatic dysfunction plays a role in regulating tumor microenvironments and may be therapeutically targeted in combination with immunotherapy to prevent tumor growth and progression.

DOI10.1158/2326-6066.CIR-18-0337
Alternate JournalCancer Immunol Res
PubMed ID31186247
PubMed Central IDPMC6677612
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R01 HL111130 / HL / NHLBI NIH HHS / United States
T32 CA009501 / CA / NCI NIH HHS / United States