Corresponding Author: C. Marcela Diaz-Montero, Ph.D., Department Immunology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195. Conflict of interest: BR has received consulting fees from and performed contracted research for Bristol-Myers Squibb, GlaxoSmithKline, Merck, and Pfizer. Additionally, he has performed contracted research for Genentech. The remaining authors declare no conflict of interest. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptPurpose-Little is known about the association between MDSC subsets and various chemokines in patients with RCC, or the factors that draw MDSC into tumor parenchyma.Experimental Design-We analyzed PMN-MDSC, M-MDSC and I-MDSC from the parenchyma and peripheral blood of 48 RCC patients, isolated at nephrectomy. We analyzed levels of IL-1β, IL-8, CXCL5, Mip-1α, MCP-1 and Rantes. Furthermore, we performed experiments in a Renca murine model to assess therapeutic synergy between CXCL2 and anti-PD1, and to elucidate the impact of IL-1β blockade on MDSC. Results-Parenchymal

The role of tumor-produced chemokines in the growth of malignancies remains poorly understood. We retrieved an in vivo growing MCA205 fibrosarcoma and isolated tumor cell clones that produce both CXCL9/monokine induced by IFN-γ (Mig) and CXCL10/IFN-γ-inducible protein 10 following stimulation with IFN-γ and clones that produce IFN-γ-inducible protein 10 but not Mig. The Mig-deficient variants grew more aggressively as cutaneous tumors in wild-type mice than the Mig-producing tumor cells. The growth of Mig-expressing, but not Mig-deficient, tumor cells was suppressed by NK and T cell activity. Transduction of Mig-negative variants to generate constitutive tumor cell production of Mig resulted in T cell-dependent rejection of the tumors and in induction of protective tumor-specific CD8+ T cell responses to Mig-deficient tumors. The results indicate a critical role for tumor-derived Mig in T cell-mediated responses to cutaneous fibrosarcomas and suggest the loss of Mig expression as a mechanism used by tumor cells to evade these responses.

Here we report that glioblastoma multiforme (GBM) mediates immunosuppression by promoting T-cell death via tumorassociated CD70 and gangliosides that act through receptordependent and receptor-independent pathways, respectively. GBM lines cocultured with T cells induced lymphocyte death. The GBM lines were characterized for their expression of CD70, Fas ligand (FasL), and tumor necrosis factor-A (TNF-A), and the possible participation of those molecules in T-cell killing was assessed by doing GBM/T cell cocultures in the presence of anti-CD70 antibodies, Fas fusion proteins, or anti-TNF-A antibodies. CD70 but not TNF-A or FasL is responsible for initiating T-cell death via the receptor-dependent pathway. Of the four GBM cell lines that induced T-cell death, three highly expressed CD70. Two nonapoptogenic GBM lines (CCF3 and U138), on the other hand, had only minimally detectable CD70 expression. Blocking experiments with the anti-CD70 antibody confirmed that elevated CD70 levels were involved in the apoptogenicity of the three GBM lines expressing that molecule. Gangliosides were found to participate in the induction of T-cell apoptosis, because the glucosylceramide synthase inhibitor (PPPP) significantly reduced the abilities of all four apoptogenic lines to kill the lymphocytes. Highperformance liquid chromatography (HPLC) and mass spectroscopy revealed that GM2, GM2-like gangliosides, and GD1a were synthesized in abundance by all four apoptogenic GBM lines but not by the two GBMs lacking activity. Furthermore, gangliosides isolated from GBM lines as well as HPLC fractions containing GM2 and GD1a were directly apoptogenic for T cells. Our results indicate that CD70 and gangliosides are both products synthesized by GBMs that may be key mediators of T-cell apoptosis and likely contribute to the T-cell dysfunction observed within the tumor microenvironment. (Cancer Res 2005; 65(12): 5428-38)

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Cancer patients often exhibit loss of proper cell-mediated immunity and reduced effector T-cell population in the circulation. Thymus is a major site of T-cell maturation, and tumors induce thymic atrophy to evade cellular immune response. Here, we report severe thymic hypocellularity along with decreased thymic integrity in tumor bearer. In an effort to delineate the mechanisms behind such thymic atrophy, we observed that tumor-induced oxidative stress played a critical role, as it perturbed nuclear factor-KB (NF-KB) activity. Tumor-induced oxidative stress increased cytosolic IKBA retention and inhibited NF-KB nuclear translocation in thymic T cells. These NF-KB-perturbed cells became vulnerable to tumor-secreted tumor necrosis factor (TNF)-A (TNF-A)-mediated apoptosis through the activation of TNF receptorassociated protein death domain-associated Fas-associated protein death domain and caspase-8. Interestingly, TNF-Adepleted tumor supernatants, either by antibody neutralization or by TNF-A-small interfering RNA transfection of tumor cells, were unable to kill T cell effectively. When T cells were overexpressed with NF-KB, the cells became resistant to tumor-induced apoptosis. In contrast, when degradationdefective IKBA (IKBA super-repressor) was introduced into T cells, the cells became more vulnerable, indicating that inhibition of NF-KB is the reason behind such tumor/TNF-Amediated apoptosis. Curcumin could prevent tumor-induced thymic atrophy by restoring the activity of NF-KB. Further investigations suggest that neutralization of tumor-induced oxidative stress and restoration of NF-KB activity along with the reeducation of the TNF-A signaling pathway can be the mechanism behind curcumin-mediated thymic protection. Thus, our results suggest that unlike many other anticancer agents, curcumin is not only devoid of immunosuppressive effects but also acts as immunorestorer in tumor-bearing host.