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Successful Immunotherapy with IL-2/Anti-CD40 Induces the Chemokine-Mediated Mitigation of an Immunosuppressive Tumor Microenvironment

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Successful Immunotherapy with IL-2/Anti-CD40 Induces the Chemokine-Mediated Mitigation of an Immunosuppressive Tumor Microenvironment Successful immunotherapy with IL-2/anti-CD40 induces the chemokine-mediated mitigation of an immunosuppressive tumor microenvironment Jonathan M. Weissa, Timothy C. Backa, Anthony J. Scarzelloa, Jeff J. Subleskia, Veronica L. Halla, Jimmy K. Stauffera, Xin Chena, Dejan Micica, Kory Aldersonb, William J. Murphyb, and Robert H. Wiltrouta,1 aLaboratory of Experimental Immunology, Cancer and Inflammation Program, NCI Frederick, Frederick, MD 21702; and bDepartment of Dermatology, University of California, Davis, CA 95616 Edited by Thomas A. Waldmann, National Institutes of Health, Bethesda, MD, and approved September 28, 2009 (received for review August 25, 2009) Treatment of mice bearing orthotopic, metastatic tumors with associated with the recruitment of mononuclear cells capable of anti-CD40 antibody resulted in only partial, transient anti-tumor producing tumor promoting factors (8, 9), as well as MDSC that effects whereas combined treatment with IL-2/anti-CD40, induced contribute to tumor progression through the inhibition of effec- tumor regression. The mechanisms for these divergent anti-tumor tor cell functions (8, 10). responses were examined by profiling tumor-infiltrating leukocyte We reported previously that IL-2 and agonistic antibody to subsets and chemokine expression within the tumor microenvi- CD40 (␣CD40) synergize for the regression of metastatic tumors ronment after immunotherapy. IL-2/anti-CD40, but not anti-CD40 in mice (11). Although we identified CD8ϩ T cells and host IFN␥ alone, induced significant infiltration of established tumors by NK expression as critical components of this therapeutic approach -and CD8؉ T cells. To further define the role of chemokines in (11), the specific mechanisms underlying the IL-2/␣CD40 syn leukocyte recruitment into tumors, we evaluated anti-tumor re- ergistic anti-tumor responses within the microenvironment re- sponses in mice lacking the chemokine receptor, CCR2. The anti- main unclear. We demonstrate in a murine model of metastatic tumor effects and leukocyte recruitment mediated by anti-CD40 renal cancer that ␣CD40 may be limited by its dependency upon ؊ ؊ alone, were completely abolished in CCR2 / mice. In contrast, MCP-1 and an inability to remove Tregs and MDSC specifically IL-2/anti-CD40-mediated leukocyte recruitment and reductions in from within the tumor microenvironment, allowing for eventual ؊ ؊ primary tumors and metastases were maintained in CCR2 / mice. tumor progression. In contrast, synergistic anti-tumor responses Treatment of mice with IL-2/anti-CD40, but not anti-CD40 alone, and protection achieved by IL-2/␣CD40 are associated with the also caused an IFN-␥-dependent increase in the expression of expression of Th1 chemokines that are associated with favorable multiple Th1 chemokines within the tumor microenvironment. prognosis in RCC (5, 6), an augmentation of effector leukocytes Interestingly, although IL-2/anti-CD40 treatment increased Tregs in and concomitant removal of suppressive cells specifically within ␥ the spleen, it also caused a coincident IFN- -dependent reduction the tumor microenvironment. in CD4؉/FoxP3؉ Tregs, myeloid-derived suppressor cells and Th2 chemokine expression specifically within the tumor microenviron- Results ment that was not observed after treatment with anti-CD40 alone. CCR2 Expression Is Required for ␣CD40, but Not IL-2/␣CD40 Mediated Similar effects were observed using IL-15 in combination with Anti-Tumor Responses. Our previous study showed that IL-2/ anti-CD40. Taken together, our data demonstrate that IL-2/anti- ␣CD40 exhibited strong synergy for treatment of established CD40, but not anti-CD40 alone, can preferentially reduce the metastatic tumors in mice, as compared to IL-2 or ␣CD40 as overall immunosuppressive milieu within the tumor microenviron- single agents (11). Furthermore, we found that ␣CD40 treatment ment. These results suggest that the use of anti-CD40 in combina- of Renca-bearing mice induced significant reduction in tumors IMMUNOLOGY tion with IL-2 or IL-15 may hold substantially more promise for in association with high levels of systemic MCP-1 levels, sug- clinical cancer treatment than anti-CD40 alone. gesting a possible role for MCP-1 in leukocyte recruitment into ͉ ͉ tumors and CD40-dependent anti-tumor effects (12). To deter- chemokines tumor immunotherapy CD40 mine the relative contribution of MCP-1 to the ␣CD40- and IL-2/␣CD40-mediated anti-tumor responses, we compared tu- any strategies for cancer treatment use combinations of mor outcomes in treated WT and mice deficient in CCR2, the Mimmunotherapeutic agents for enhanced anti-tumor re- receptor for MCP-1 (13). Treatment of WT mice with ␣CD40 sponses. However, these approaches are often complicated by a significantly reduced primary tumor areas, but a substantially need to overcome tumor-induced immune suppression in the greater reduction was observed after IL-2/␣CD40 treatment tumor microenvironment. In this regard, T regulatory (Treg) (Fig. 1A). Interestingly, the effects of ␣CD40 were abrogated in cells and myeloid-derived suppressor cells (MDSC) have been CCR2Ϫ/Ϫ mice, whereas the efficacy of IL-2/␣CD40 treatment identified as functional suppressor cells within tumors (1, 2). The was maintained in CCR2Ϫ/Ϫ mice. most effective immunotherapeutic regimens are likely to consist Since the orthotopic tumor model that we used forms spon- of agents that restructure, within the tumor microenvironment, taneous tumor metastases in the lungs, we next examined the the composition of tumor-infiltrating leukocytes away from these inhibitory elements in favor of effector cells, such as NK ϩ cells and CD8 T cells. Author contributions: J.M.W. designed research; J.M.W., T.C.B., X.C., and D.M. performed Chemokine expression can regulate the polarization of im- research; A.J.S., J.J.S., V.L.H., and J.K.S. contributed new reagents/analytic tools; J.M.W., mune responses (3). For example, CXCR3 and CCR5 are A.J.S., V.L.H., K.A., W.J.M., and R.H.W. analyzed data; and J.M.W. wrote the paper. preferentially expressed on Th1 T cells and M1 macrophages and The authors declare no conflict of interest. their respective ligands are associated with enhanced cell- This article is a PNAS Direct Submission. mediated immune responses (3–5) and favorable prognosis in Freely available online through the PNAS open access option. human RCC (5, 6). Another chemokine, monocyte chemoat- 1To whom correspondence should be addressed. E-mail: [email protected]. tractant protein (MCP)-1 activates macrophages for enhanced This article contains supporting information online at www.pnas.org/cgi/content/full/ anti-tumor activities (7), however MCP-1 expression is also 0909474106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0909474106 PNAS ͉ November 17, 2009 ͉ vol. 106 ͉ no. 46 ͉ 19455–19460 Downloaded by guest on September 30, 2021 Fig. 2. ␣CD40 induces CCR2-dependent leukocyte recruitment into tumors, whereas IL-2/␣CD40 maximally induces CCR2-independent increases in tumor- infiltrating leukocytes. (A) Wild-type and (B) CCR2Ϫ/Ϫ tumor-bearing mice Fig. 1. CCR2 is required for ␣CD40, but not IL-2/␣CD40-mediated anti-tumor were treated, as indicated. On day 22, mice were euthanized and the primary responses. (A) WT and CCR2Ϫ/Ϫ tumor-bearing mice were treated as indicated. tumor was dissected. Total leukocytes were counted and further identified by On day 22, mice were euthanized, the primary tumor was dissected and cell surface staining with the indicated antibodies and flow cytometry. The measured. (B) Lungs from these treated mice were collected on the same day total number of each cell subset was calculated by multiplying the total Ͻ and fixed in Bouin’s solution. The number of lung metastases was counted number of leukocytes by the percent expressing each surface marker (*, P 0.05; NS ϭ not significant). Data are derived from two tumors per treatment under a dissecting microscope (*, P Ͻ 0.05 and **, P Ͻ 0.005 as compared to control-treated mice). (C) For studies of tumor progression, mice underwent group in each of three separate experiments. surgical removal of the tumor-bearing kidney followed by treatment with IL-2 ␣ and/or CD40. Survival analysis was plotted according to the Kaplan-Meier ␣ method and statistical differences determined using the log-rank test (*, P Ͻ (Fig. S2). Thus, as compared to IL-2 or CD40 alone, IL-2/ 0.0001). For all tumor studies, the results from one experiment consisting of 10 ␣CD40 maximally enhances leukocyte recruitment into the mice/treatment group are shown and results are representative of three tumor microenvironment. similar experiments. To determine the relative contribution of MCP-1 to the ␣CD40- and IL-2/␣CD40-mediated leukocyte recruitment into tumors, we analyzed the profile of leukocytes in treated ␣ ␣ effect of CD40 and IL-2/ CD40 treatment on lung metastases. CCR2Ϫ/Ϫ mice (Fig. 2B). The IL-2/␣CD40 mediated increases ␣ ϩ Similar to primary tumors, CD40 alone significantly reduced in CD8 T cells, B cells and macrophages were maintained in Ϫ/Ϫ the number of metastases in WT, but not CCR2 mice (Fig. CCR2Ϫ/Ϫ mice. In contrast, the ␣CD40-mediated increase in 1B). In contrast, the reduction in metastases achieved by IL-2/ macrophages was lost in CCR2Ϫ/Ϫ mice (Fig. 2B). We also found ␣ Ϫ/Ϫ CD40 was maintained in CCR2 mice. that NK cell recruitment in response to IL-2/␣CD40 was abol- To evaluate the efficacy of the different treatments on survival ished in CCR2Ϫ/Ϫ mice. of mice bearing metastatic disease, we performed a unilateral The results above were further confirmed by immunohisto- nephrectomy of the tumor-bearing kidney, followed by treatment of Ϫ/Ϫ Ϫ Ϫ chemical analyses on tumors from treated WT or CCR2 mice residual metastatic disease. IL-2/␣CD40-treated WT and CCR2 / (Fig. S3). Whereas IL-2/␣CD40 indued macrophage and CD8ϩ mice had significantly prolonged survival, with Ͼ75% of the mice T cell recruitment in WT and CCR2Ϫ/Ϫ mice, the ␣CD40- remaining disease-free for Ͼ80 days (Fig.
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