PD‐1/PD‐L1 immune checkpoint inhibitors are promising cancer immunotherapies however responses are still limited and the development of more effective combination immunotherapy is needed. We previously reported that STAT3 activation in cancer cells and immune cells was involved in immune‐resistant mechanisms. In this study, we evaluated the effect of highly absorptive forms of curcumin extracts and synthetic curcumin on anti‐tumor T cell responses. The curcumin po administration resulted in the significant augmentation of in vivo induction of tumor antigen‐specific T cells through restoration of dendritic cells (DCs) by inhibiting directly STAT3 in DCs and indirectly via reduced IL‐6 production from STAT3 activated cancer cells in 2 syngeneic MC38 and CT26 murine tumor models. Curcumin also showed direct DC enhancing activity and enhanced T cell induction for the immunized antigens in non‐tumor‐bearing mice and human hosts. Curcumin restored DC functions in xenogeneic nude mouse model implanted with high IL‐6‐producing human clear cell ovarian cancer cells. The combination of curcumin and PD‐1/PD‐L1 Abs demonstrated a synergistic anti‐tumor activity in MC38 murine tumor models. These results indicated that curcumin augments the induction of tumor antigen‐specific T cells by restoring the T cell stimulatory activity of DCs targeting activated STAT3 in both cancer cells and immune cells. Combination immunotherapy with curcumin and PD‐1/PD‐L1 Ab is an attractive strategy in the development of effective immunotherapy against various cancers.

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The terminology "Peierls distortion ͑PD͒" has been widely accepted in disordered systems ever since the discovery of PD in liquid As ͓R. Bellissent et al., Phys. Rev. Lett. 59, 661 ͑1987͔͒. It has not been clarified, however, to what extent the PD in liquids mirrors the PD in crystals. Here we report the observation on the pressure-induced suppression of PD in liquid As and liquid GeX ͑X =S,Se,Te͒, by which we clarified the qualitative differences as well as similarities between the PD of liquid and crystalline systems. By the appearance of prepeak that accompanies PD, we show that the intermediate-range order is related to the "Peierls distortion" in liquids, just as the Peierls distortion doubles the periodicity in one-dimensional lattice model.

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X-ray diffraction of liquid CuI, CuBr and CuCl has been measured up to 19 GPa using synchrotron radiations. Static structure factor S(Q) and pair distribution function g(r) were obtained. For liquid CuI, CuBr and CuCl, S(Q) and g(r) change their shapes continuously with increasing pressure, indicating anisotropic compression of the local structures. The pressure dependence of the peak position ratio r(2)/r(1) of g(r) shows that Cu atoms are located in a tetrahedral site at low pressures and then in an octahedral site at high pressures in these liquid copper halides. At higher pressures, the local structure of liquid CuCl is similar to the intermediate structure between NaCl and CsCl structures. These results are compared with the pressure-induced structural transformation in the crystalline phase.

The PD-1/PD-L1 blockade is now recognized as one of the basic immune interventions for development of combination cancer immunotherapy. We have been screening chemical libraries to obtain compounds which have an activity to augment anti-tumor activity of the PD-1/PD-L1 blockade. We have previously shown that activation of NF-kB and STAT3 signals in both cancer cells and immune cells plays important roles in cancer cell-induced immunosuppression, and their inhibition may augment anti-tumor CTL. Curcumin, a major active component of turmeric, has activities to inhibit both NF-kB and STAT3 signals. We have recently developed a highly absorptive form of curcumin which oral administration resulted in high plasma concentration. In this study, we evaluated combination treatment of this highly absorptive form of curcumin with the PD-1/PD-L1 blockade. Curcumin inhibited significantly in vitro production of IL6 and IL8 by human ovarian cancer cell lines (OC) having activated NF-kB and STAT3 signaling. In nude mice implanted with human OC, T-cell stimulatory activity of murine DC was impaired partly through increased human IL-6 from human OC. Systemic p.o. administration of curcumin decreased human IL6 in mouse serum and restored T-cell stimulatory activity of murine DC in spleens and tumors. In two syngeneic murine colon cancer models, NF-kB dependent IL6 producing MC38 in B6 mice and NF-kB non-activated IL6 non-producing CT26 in Balb/C mice, curcumin p.o. administration resulted in the significant augmentation of tumor antigen-specific CD8+ T-cell induction accompanied by increased T-cell stimulatory activity of DC via decreased STAT3 and NF-kB signaling, although curcumin did not inhibit proliferation of both tumor cell lines. Furthermore, p.o. administration of curcumin into non-tumor bearing B6 mice immunized with ovalbumin (OVA) peptide augmented OVA-specific CTL induction. These results indicate that curcumin not only enhances tumor antigen specific T-cell via reversal of tumor-induced immunosuppression (e.g. IL6 induced DC impairment), but also enhances CTL via directly acting on immune cells. Since PD-1 positive T cells were infiltrated in tumors expressing PD-L1, we evaluated combination of curcumin and anti-PD-L1 blockade, and found that combination of curcumin and anti-PD-L1 Ab had synergistic anti-tumor activity. These results indicate that combination of curcumin which enhances induction of tumor antigen specific, PD-1 positive CTL in tumors via acting on both cancer cells and immune cells and local PD-1/PD-L1 blockade, is an attractive strategy for development of effective cancer immunotherapy.