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.

Purpose: Relapsed or refractory Hodgkin lymphoma is a challenge for medical oncologists because of poor overall survival. We aimed to assess the feasibility, safety, and efficacy of CD30-targeting CAR T cells in patients with progressive relapsed or refractory Hodgkin lymphoma. Experimental Design: Patients with relapsed or refractory Hodgkin lymphoma received a conditioning chemotherapy followed by the CART-30 cell infusion. The level of CAR transgenes in peripheral blood and biopsied tumor tissues was measured periodically according to an assigned protocol by quantitative PCR (qPCR). Results: Eighteen patients were enrolled; most of whom had a heavy treatment history or multiple tumor lesions and received a mean of 1.56 × 107 CAR-positive T cell per kg (SD, 0.25; range, 1.1–2.1) in total during infusion. CART-30 cell infusion was tolerated, with grade ≥3 toxicities occurring only in two of 18 patients. Of 18 patients, seven achieved partial remission and six achieved stable disease. An inconsistent response of lymphoma was observed: lymph nodes presented a better response than extranodal lesions and the response of lung lesions seemed to be relatively poor. Lymphocyte recovery accompanied by an increase of circulating CAR T cells (peaking between 3 and 9 days after infusion) is a probable indictor of clinical response. Analysis of biopsied tissues by qPCR and immunohistochemistry revealed the trafficking of CAR T cells into the targeted sites and reduction of the expression of CD30 in tumors. Conclusions: CART-30 cell therapy was safe, feasible, and efficient in relapsed or refractory lymphoma and guarantees a large-scale patient recruitment. Clin Cancer Res; 23(5); 1156–66. ©2016 AACR.

The MetS is highly prevalent in elderly people in Beijing, particularly among women. Individuals with MetS defined by either criteria are at significantly elevated ORs for CHD, stroke, and PAD. The IDF criteria seem to be better suited than the NCEP criteria for screening and estimating risk of MetS in Chinese people.

Anti-PD-1 treatment has shown unprecedented clinical success in the treatment of non-small-cell lung cancer (NSCLC), but the underlying mechanisms remain incompletely understood. Here, we performed temporal single-cell RNA and paired T-cell receptor sequencing on 47 tumor biopsies from 36 patients with NSCLC following PD-1-based therapies. We observed increased levels of precursor exhausted T (Texp) cells in responsive tumors after treatment, characterized by low expression of coinhibitory molecules and high expression of GZMK. By contrast, nonresponsive tumors failed to accumulate Texp cells. Our data suggested that Texp cells were unlikely to be derived from the reinvigoration of terminally exhausted cells; instead, they were accumulated by (1) local expansion and (2) replenishment by peripheral T cells with both new and pre-existing clonotypes, a phenomenon we named clonal revival. Our study provides insights into mechanisms underlying PD-1-based therapies, implicating clonal revival and expansion of Texp cells as steps to improve NSCLC treatment.