Lactate is a key metabolite produced from glycolytic metabolism of glucose molecules, yet it also serves as a primary carbon fuel source for many cell types. In the tumor-immune microenvironment, effect of lactate on cancer and immune cells can be highly complex and hard to decipher, which is further confounded by acidic protons, a co-product of glycolysis. Here we show that lactate is able to increase stemness of CD8⁺ T cells and augments anti-tumor immunity. Subcutaneous administration of sodium lactate but not glucose to mice bearing transplanted MC38 tumors results in CD8⁺ T cell-dependent tumor growth inhibition. Single cell transcriptomics analysis reveals increased proportion of stem-like TCF-1-expressing CD8⁺ T cells among intra-tumoral CD3⁺ cells, a phenotype validated by in vitro lactate treatment of T cells. Mechanistically, lactate inhibits histone deacetylase activity, which results in increased acetylation at H3K27 of the Tcf7 super enhancer locus, leading to increased Tcf7 gene expression. CD8⁺ T cells in vitro pre-treated with lactate efficiently inhibit tumor growth upon adoptive transfer to tumor-bearing mice. Our results provide evidence for an intrinsic role of lactate in anti-tumor immunity independent of the pH-dependent effect of lactic acid, and might advance cancer immune therapy.

Export of lactic acid from glycolytic cancer cells to the extracellular tumor milieu has been reported to enhance tumor growth and suppress antitumor immunity. In this study, a pH‐activatable nanodrug is reported for tumor‐targeted inhibition of monocarboxylate transporter‐1 (MCT1) that reverses lactic acid‐induced tumor immunosuppression. The nanodrug is composed of an MCT1 inhibitor (AZD3965) loaded inside the ultra‐pH‐sensitive nanoparticles (AZD‐UPS NPs). AZD‐UPS NP is produced by a microfluidics method with improved drug loading efficiency and optimal nanoparticle size over sonication methods. The nanodrug remains as intact micelles at pH 7.4 but rapidly disassembles and releases payload upon exposure to acidic pH. When combined with anti‐PD‐1 therapy, AZD‐UPS NP leads to potent tumor growth inhibition and increases survival in two tumor models over oral administration of AZD3965 at dramatically reduced dose (>200‐fold). Safety evaluations demonstrate reduced drug distribution in heart and liver tissues with decrease in toxic biomarkers such as cardiac troponin by the nanodrug. Increased T‐cell infiltration and reduced exhaustive PD1⁺Tim3⁺ T cells are found in tumors. These data illustrate that tumor‐targeted inhibition of MCT1 can reverse the immune suppressive microenvironment of solid tumors for increased safety and antitumor efficacy of cancer immunotherapy.

Solitary cysticercus granuloma (SCG) is the commonest form of neurocysticercosis in the Indian subcontinent and in travelers. Several different treatment options exist for SCG. We conducted a Bayesian network meta-analysis of randomized clinical trials (RCTs) to identify the best treatment option to prevent seizure recurrence and promote lesion resolution for patients with SCG. PubMed, EMBASE and the Cochrane Library databases (up to June 1, 2015) were searched for RCTs that compared any anthelmintics or corticosteroids, alone or in combination, with placebo or head to head and reported on seizure recurrence and lesion resolution in patients with SCG. A total of 14 RCTs (1277 patients) were included in the quantitative analysis focusing on four different treatment options. A Bayesian network model computing odds ratios (OR) with 95% credible intervals (CrI) and probability of being best (P_best) was used to compare all interventions simultaneously. Albendazole and corticosteroids combination therapy was the only regimen that significantly decreased the risk of seizure recurrence compared with conservative treatment (OR 0.32, 95% CrI 0.10–0.93, P_best 73.3%). Albendazole and corticosteroids alone or in combination were all efficacious in hastening granuloma resolution, but the combined therapy remained the best option based on probability analysis (OR 3.05, 95% CrI 1.24–7.95, P_best 53.9%). The superiority of the combination therapy changed little in RCTs with different follow-up durations and in sensitivity analyses. The limitations of this study include high risk of bias and short follow-up duration in most studies. Dual therapy of albendazole and corticosteroids was the most efficacious regimen that could prevent seizure recurrence and promote lesion resolution in a follow-up period of around one year. It should be recommended for the management of SCG until more high-quality evidence is available. Neurocysticercosis is an infection of the central nervous system by the larva of Taenia solium (pork tapeworm). It is a leading cause of epilepsy in the world. The disease takes many different forms, each with different optimal treatment. In this study, we focused on the treatment of solitary cysticercus granuloma (SCG), previous evidence on which is inconclusive. Since many different regimens have been compared in clinical trials of SCG, we conducted a network meta-analysis. This method is powerful as it can analyze quantitatively all of the data from all comparisons together. The result can tell us how different treatments perform against each other and how treatments should be ranked. The outcomes of our meta-analysis suggest that the combination of albendazole and corticosteroids is the most efficacious regimen to control seizures in affected patients and to promote the total disappearance of the lesion, compared with albendazole alone, corticosteroids alone, and conservative treatment.

Hepatocellular carcinomas (HCC) arising in the caudate lobe is rare and the treatment is difficult. The aim of this study is to summarize the experience of ultrasound-guided percutaneous ablation therapy for HCC located in the caudate lobe and to investigate the predictive factors of the treatment outcomes. From August 2006 to June 2017, 73 patients (63 males and 10 females; mean age, 54.9 ± 11.6 years; age range, 25–79 years) with 73 caudate lobe HCCs (mean size, 2.6 ± 1.1 cm; size range, 1.0–5.0 cm) were treated with percutaneous ablation, including 33 patients with radiofrequency ablation (RFA), 23 patients with ethanol ablation (EA), and 17 patients with combination of RFA and EA. The treatment outcome and survival after ablation for caudate lobe HCC were assessed and the predictive factors were calculated by univariate and multivariate analyses. A total of 72 patients achieved complete ablation after the first or second session of ablation. The treatment effectiveness was 98.6% (72/73). During the follow-up, 16 tumors developed local tumor progression (LTP) and a total of 61 patients (61/73, 83.6%) were detected distant recurrence (DR). According to univariate and multivariate analyses, tumor size > 2 cm (hazard ratio[HR] = 3.667; 95% confidence interval[CI], 1.043–12.889; P = 0.043) was a significant prognostic factor of LTP after ablation for HCC in the caudate lobe, while tumor number (HR = 2.245; 95%CI, 1.168–4.317; P = 0.015) was a significant prognostic factor of DR. The mean overall survival time after ablation was 28.7 ± 2.8 months, without independent predictive factors detected. Four patients (4/73, 5.5%) were detected treatment-related major complications, without independent predictive factor detected. Ultrasound-guided percutaneous ablation is a feasible treatment for a selected case with HCC in the caudate lobe. Tumor size > 2 cm increases the risk of LTP and intrahepatic tumor number is associated with DR after ablation.