Abstract
CD8+ T cell-mediated cancer clearance is often suppressed by the interaction between inhibitory molecules like PD-1 and PD-L1, an interaction acts like brakes to prevent T cell overreaction under normal conditions but is exploited by tumor cells to escape the immune surveillance. Immune checkpoint inhibitors have revolutionized cancer therapeutics by removing such brakes. Unfortunately, only a minority of cancer patients respond to immunotherapies presumably due to inadequate immunity. Antitumor immunity depends on the activation of the cGAS-STING pathway, as STING-deficient mice fail to stimulate tumor-infiltrating dendritic cells (DCs) to activate CD8+ T cells. STING agonists also enhance natural killer (NK) cells to mediate the clearance of CD8+ T cell-resistant tumors. Therefore STING agonists have been intensively sought after. We previously discovered that manganese (Mn) is indispensable for the host defense against cytosolic dsDNA by activating cGAS-STING. Here we report that Mn is also essential in innate immune sensing of tumors and enhances adaptive immune responses against tumors. Mn-insufficient mice had significantly enhanced tumor growth and metastasis, with greatly reduced tumor-infiltrating CD8+ T cells. Mechanically, Mn2+ promoted DC and macrophage maturation and tumor-specific antigen presentation, augmented CD8+ T cell differentiation, activation and NK cell activation, and increased memory CD8+ T cells. Combining Mn2+ with immune checkpoint inhibition synergistically boosted antitumor efficacies and reduced the anti-PD-1 antibody dosage required in mice. Importantly, a completed phase 1 clinical trial with the combined regimen of Mn2+ and anti-PD-1 antibody showed promising efficacy, exhibiting type I IFN induction, manageable safety and revived responses to immunotherapy in most patients with advanced metastatic solid tumors. We propose that this combination strategy warrants further clinical translation.
Highlights
The immune system recognizes and kills tumor cells, in which the innate immunity is mainly responsible for the detection of tumor cells and the activation of adaptive immunity
Mn is essential for antitumor immune responses Since we previously found that Mn was critically involved in innate immune sensing of cytosolic double-stranded DNA (dsDNA) to activate the cGAS-STING pathway, which is important for exerting antitumor immune responses, we hypothesized that Mn would play roles in innate immune responses against tumor cells
Intravenously inoculated B16F10 cells in Mn-insufficient mice induced much stronger lung metastasis, compared to the control Mn-sufficient mice (Fig. 1k). These results demonstrated Mn is critical in maintaining the host antitumor immune responses and strongly suggested that Mn is important for preventing tumorigenesis under physiological conditions
Summary
The immune system recognizes and kills tumor cells, in which the innate immunity is mainly responsible for the detection of tumor cells and the activation of adaptive immunity. Clearance of tumor cells is often introverted by the interaction between the inhibitory checkpoint molecules like the programmed cell death protein-1 (PD-1)[1,2] and its ligand such as PD-L1,3 an interaction like a brake to prevent T cell overreaction under normal conditions. PD-L1 or CTLA-4 blocking antibodies have revolutionized cancer therapeutics by removing such inhibitory brakes,[4,5] the effectiveness of which depends on the recognition of tumor-specific antigens to generate and activate tumor-specific CD8+ T cells ( known as cytotoxic T cells, CTLs). NK cells have been found to mediate the clearance of CD8+ T cell-resistant tumors.[6] only about 20% of cancer patients respond to immunotherapies presumably due to inadequate immune activation.[5,7,8]
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