Immune dysfunction is well documented during tumor progression and likely contributes to tumor immune evasion. CD8 1 cytotoxic T lymphocytes (CTLs) are involved in antigen-specific tumor destruction and CD4 1 T cells are essential for helping this CD8 1 T cell-dependent tumor eradication. Tumors often target and inhibit T-cell function to escape from immune surveillance. This dysfunction includes loss of effector and memory T cells, bias towards type 2 cytokines and expansion of T regulatory (Treg) cells. Curcumin has previously been shown to have antitumor activity and some research has addressed the immunoprotective potential of this plant-derived polyphenol in tumor-bearing hosts. Here we examined the role of curcumin in the prevention of tumor-induced dysfunction of T cell-based immune responses. We observed severe loss of both effector and memory T-cell populations, downregulation of type 1 and upregulation of type 2 immune responses and decreased proliferation of effector T cells in the presence of tumors. Curcumin, in turn, prevented this loss of T cells, expanded central memory T cell (T CM )/effector memory T cell (T EM ) populations, reversed the type 2 immune bias and attenuated the tumor-induced inhibition of T-cell proliferation in tumor-bearing hosts. Further investigation revealed that tumor burden upregulated Treg cell populations and stimulated the production of the immunosuppressive cytokines transforming growth factor (TGF)-b and IL-10 in these cells. Curcumin, however, inhibited the suppressive activity of Treg cells by downregulating the production of TGF-b and IL-10 in these cells. More importantly, curcumin treatment enhanced the ability of effector T cells to kill cancer cells. Overall, our observations suggest that the unique properties of curcumin may be exploited for successful attenuation of tumor-induced suppression of cell-mediated immune responses.

Patients with advanced cancer exhibit multifaceted defects in their immune capacity, which are likely to contribute to an increased susceptibility to infections and disease progression. We demonstrated earlier that curcumin inhibits tumor growth and prevents immune cell death in tumor-bearing hosts. Here we report that tumor-induced immunodepletion involves apoptosis of thymic CD4 ؉ /CD8 ؉ single/double positive cells as well as loss of circulating CD4؉ /CD8 ؉ T cells. Administration of curcumin to tumor-bearing animals resulted in restoration of progenitor, effecter, and circulating T cells. In fact, tumor burden decreased the expression level of the pro-proliferative protein Bcl-2 while increasing the pro-apoptotic protein Bax in T cells. Curcumin down-regulated the Bax level while augmenting Bcl-2 expression in these cells, thereby protecting the immunocytes from tumor-induced apoptosis. A search for the upstream mechanism revealed down-regulation of the common cytokine receptor ␥ chain (␥c) expression in T cells by tumor-secreted prostaglandin E 2 . As a result, Jak-3 and Stat-5a phosphorylation and to a lesser extent Stat-5b phosphorylation were also decreased in T cells. These entire phenomena could be reverted back by curcumin, indicating that this phytochemical restored the cytokine-dependent Jak-3/Stat-5a signaling pathway in T cells of tumor bearers. Overexpressed Stat-5a/constitutively active Stat-5a1*6 but not Stat-5b could efficiently elevate Bcl-2 levels and protect T cells from tumor-induced death, whereas C-terminal truncated Stat-5a 713 overexpression failed to do so, indicating the importance of Stat-5a signaling in T cell survival. Thus, these results raise the possibility of inclusion of curcumin in successful therapeutic regimens against cancer.

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.

Background: Constitutive activation of NFB has been found in various cancers, causing resistance to chemotherapeutic drugs. Results: Curcumin pretreatment alleviates p65NFB activation and hence tailors p65NFB-p300 cross-talk in favor of p53-p300 in drug-resistant cells. Conclusion:This preclinical study suggests curcumin as a potent chemo-sensitizer to improve the therapeutic index. Significance: These results suggest that curcumin can be developed into an adjuvant chemotherapeutic drug.