Basic—Liver, Pancreas, and Biliary TractCD39/ENTPD1 Expression by CD4+Foxp3+ Regulatory T Cells Promotes Hepatic Metastatic Tumor Growth in Mice
Section snippets
Animals
Six- to 14-week-old male C57BL6 Cd39 null mice were used.8 Age-, sex-, and strain-matched wild-type (wt) mice and (γc)/Rag2−/− mice were purchased from Taconic Farms (Germantown, NY). Rag1−/− mice were from The Jackson Laboratory (Bar Harbor, ME). Foxp3-GFP (green fluorescent protein) knock-in mice were generated as described.13
Animal Experimentation Protocols were reviewed and approved by the Institutional Animal Care and Use Committees of Beth Israel Deaconess Medical Center.
Antibodies and Reagents
All chemicals
CD39 Expression Facilitates Tumor Growth
Portal vein infusion of luciferase-expressing melanoma B16/F10 (luc-B16/F10) cells and MCA38 colon cancer cells resulted in cells being retained in liver sinusoids; no tumors were found in lungs or other sites within 14 days (data not shown). Melanoma-bearing Cd39 null mice had longer times to euthanasia and death than the wt mice (P < .0001; Figure 1A).
Tumor growth in liver was substantially inhibited in Cd39 null mice (melanoma data in Figure 1B and C and colonic tumor studies in Figure 2A
Discussion
We have already shown that CD39 expression on endothelium is important for angiogenesis and is required for tumor growth in the lung.11, 18 We show now that infiltrating Tregs inhibit NK cell–mediated tumor cytotoxicity in a CD39-dependent manner in the liver. Tregs exhibit immunosuppressive effects on effector T cells, operational by adenosine-mediated pathways modulated by CD39 and CD73.9 Our current findings strengthen the notion that the expression of CD39 and associated changes in
Acknowledgments
The authors thank members of the Longwood Small Animal Imaging Facility of BIDMC for assistance with the in vivo bioluminescence imaging.
X.S. and Y.W. contributed equally to this work, and the surnames are arranged alphabetically.
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Conflicts of interest The authors disclose no conflicts.
Funding This study has been supported by the National Institutes of Health (NHLBI PO1-HL076540 and RO1-HL094400).