Title | Tumor Lymphatic Function Regulates Tumor Inflammatory and Immunosuppressive Microenvironments. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Kataru RP, Ly CL, Shin J, Park HJu, Baik JEun, Rehal S, Ortega S, Lyden D, Mehrara BJ |
Journal | Cancer Immunol Res |
Volume | 7 |
Issue | 8 |
Pagination | 1345-1358 |
Date Published | 2019 Aug |
ISSN | 2326-6074 |
Keywords | Animals, 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. |
DOI | 10.1158/2326-6066.CIR-18-0337 |
Alternate Journal | Cancer Immunol Res |
PubMed ID | 31186247 |
PubMed Central ID | PMC6677612 |
Grant List | P30 CA008748 / CA / NCI NIH HHS / United States R01 HL111130 / HL / NHLBI NIH HHS / United States T32 CA009501 / CA / NCI NIH HHS / United States |