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Successful immunotherapy with IL-2/anti-CD40 induces the chemokine-mediated mitigation of an immunosuppressive tumor microenvironment
Weiss J.M.1; Back T.C.1; Scarzello A.J.1; Subleski J.J.1; Hall V.L.1; Stauffer J.K.1; Chen X.1; Micic D.1; Alderson K.2; Murphy W.J.2; Wiltrout R.H.1
2009-11-17
Source PublicationProceedings of the National Academy of Sciences of the United States of America
ISSN00278424 10916490
Volume106Issue:46Pages:19455-19460
Abstract

Treatment of mice bearing orthotopic, metastatic tumors with anti-CD40 antibody resulted in only partial, transient anti-tumor effects whereas combined treatment with IL-2/anti-CD40, induced tumor regression. The mechanisms for these divergent anti-tumor responses were examined by profiling tumor-infiltrating leukocyte subsets and chemokine expression within the tumor microenvironment after immunotherapy. IL-2/anti-CD40, but not anti-CD40 alone, induced significant infiltration of established tumors by NK and CD8 T cells. To further define the role of chemokines in leukocyte recruitment into tumors, we evaluated anti-tumor responses in mice lacking the chemokine receptor, CCR2. The antitumor effects and leukocyte recruitment mediated by anti-CD40 alone, were completely abolished in CCR2 mice. In contrast, IL-2/anti-CD40-mediated leukocyte recruitment and reductions in primary tumors and metastases were maintained in CCR2 mice. Treatment of mice with IL-2/anti-CD40, but not anti-CD40 alone, also caused an IFN-γ-dependent increase in the expression of multiple Th1 chemokines within the tumor microenvironment. Interestingly, although IL-2/anti-CD40 treatment increased Tregs in the spleen, it also caused a coincident IFN-γ-dependent reduction in CD4/FoxP3 Tregs, myeloid-derived suppressor cells and Th2 chemokine expression specifically within the tumor microenvironment that was not observed after treatment with anti-CD40 alone. Similar effects were observed using IL-15 in combination with anti-CD40. Taken together, our data demonstrate that IL-2/anti-CD40, but not anti-CD40 alone, can preferentially reduce the overall immunosuppressive milieu within the tumor microenvironment. These results suggest that the use of anti-CD40 in combination with IL-2 or IL-15 may hold substantially more promise for clinical cancer treatment than anti-CD40 alone.

KeywordCd40 Chemokines Tumor Immunotherapy
DOIhttps://doi.org/10.1073/pnas.0909474106
URLView the original
Indexed BySCI
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000271907400043
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Cited Times [WOS]:43   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorWiltrout R.H.
Affiliation1.Laboratory of Experimental Immunology, Cancer and Inflammation Program, NCI Frederick, Frederick,
2.National Cancer Institute at Frederick
Recommended Citation
GB/T 7714
Weiss J.M.,Back T.C.,Scarzello A.J.,et al. Successful immunotherapy with IL-2/anti-CD40 induces the chemokine-mediated mitigation of an immunosuppressive tumor microenvironment[J]. Proceedings of the National Academy of Sciences of the United States of America,2009,106(46):19455-19460.
APA Weiss J.M..,Back T.C..,Scarzello A.J..,Subleski J.J..,Hall V.L..,...&Wiltrout R.H..(2009).Successful immunotherapy with IL-2/anti-CD40 induces the chemokine-mediated mitigation of an immunosuppressive tumor microenvironment.Proceedings of the National Academy of Sciences of the United States of America,106(46),19455-19460.
MLA Weiss J.M.,et al."Successful immunotherapy with IL-2/anti-CD40 induces the chemokine-mediated mitigation of an immunosuppressive tumor microenvironment".Proceedings of the National Academy of Sciences of the United States of America 106.46(2009):19455-19460.
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