Enhanced anti-tumor effects of the PD-1/PD-L1 blockade by combining a highly absorptive form of NF-kB/STAT3 inhibitor curcumin

Abstract

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.

Curcumin Micelles Remodel Tumor Microenvironment and Enhance Vaccine Activity in an Advanced Melanoma Model

“…To remodel the microenvironment, it is also necessary to get help from a drug that could play pivotal roles not only in killing tumor cells but also in dealing with the immune environment such as reducing MDSCs 13 or downregulation of STAT3. 14,15 Curcumin (CUR), a component of turmeric and one of the oldest natural polyphenols in traditional Asian medicine, is such a chemodrug. 16,17 As a well-known JAK-STAT3 pathway inhibitor, 14,15,18 CUR inhibits MDSCs in the spleen and tumor tissue in breast cancer models 19 and 3LL Lewis lung cancer models.…”

“…14,15 Curcumin (CUR), a component of turmeric and one of the oldest natural polyphenols in traditional Asian medicine, is such a chemodrug. 16,17 As a well-known JAK-STAT3 pathway inhibitor, 14,15,18 CUR inhibits MDSCs in the spleen and tumor tissue in breast cancer models 19 and 3LL Lewis lung cancer models. 20 However, its lipophilic nature and relatively low solubility in aqueous solutions create a major challenge in clinical applications as a potent anticancer agent.…”

Curcumin—A Viable Agent for Better Bladder Cancer Treatment

“…The strategy potently improved the cellular uptake and cytotoxicity of curcumin [76]. The combination of curcumin and an anti-PDL1 antibody was found to exert synergistic anti-tumor activity in an ovarian cancer mouse model, indicating that curcumin may indeed serve as an integrative component of current immunotherapy [77]. Meanwhile, a multi-center, open-label, non-randomized, 3-cohort phase 2 study has enrolled patients with recurrent/refractory cervical carcinoma, endometrial carcinoma, or uterine sarcoma.…”

Phytochemicals in Cancer Immune Checkpoint Inhibitor Therapy

“…Moreover, Hayakawa et al found that curcumin administration in the colon cancer mouse model significantly increased the tumor antigen-specific CD8 + T cell induction as well as enhanced the T cell stimulatory activity of dendritic cells (DCs) by downregulating NF-κB and STAT3 signaling pathways. They also revealed that combining curcumin with an anti-PD-L1 antibody had a synergistic tumor-suppressive effect [110]. Shao et al established mouse models bearing subcutaneous or metastatic bladder cancer and found that bisdemethoxycurcumin, an analog of curcumin, in combination treatment with an anti-PD-L1 antibody could significantly upregulate the secretion of IFN-γ and granzyme B and decrease the number of MDSCs, which successfully boosted immune response and prolonged mouse survival [113].…”