Successful immunotherapy with IL-2/anti-CD40 induces the chemokine-mediated mitigation of an immunosuppressive tumor microenvironment

Jonathan M. Weiss, Timothy C. Back, Anthony J. Scarzello, Jeff J. Subleski, Veronica L. Hall, Jimmy K. Stauffer, Xin Chen, Dejan Micic, Kory Alderson, William J Murphy, Robert H. Wiltrout

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46 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)19455-19460
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number46
DOIs
StatePublished - Nov 17 2009

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Keywords

  • CD40
  • Chemokines
  • Tumor immunotherapy

ASJC Scopus subject areas

  • General

Cite this

Weiss, J. M., Back, T. C., Scarzello, A. J., Subleski, J. J., Hall, V. L., Stauffer, J. K., Chen, X., Micic, D., Alderson, K., Murphy, W. J., & 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. https://doi.org/10.1073/pnas.0909474106