Toll-like receptor (TLR) agonists demonstrate therapeutic promise as immunological adjuvants for anticancer immunotherapy. To date, three TLR agonists have been approved by US regulatory agencies for use in cancer patients. Additionally, the potential of hitherto experimental TLR ligands to mediate clinically useful immunostimulatory effects has been extensively investigated over the past few years. Here, we summarize recent preclinical and clinical advances in the development of TLR agonists for cancer therapy.

Immune checkpoint blockade involves the targeted antagonism of immunosuppressive interactions between antigen-presenting cells and/or tumor cells and effector T cells. Blockade of B7-H1, also known as programmed death-ligand 1 (PD-L1), prevents the ligation of inhibitory PD-L1 molecules to programmed cell death receptor 1 (PD-1) on T cells, engendering a potentiated response of tumor-specific T cells against tumor cells. In a Cancer Research article, Hirano and colleagues showed that T-cell–mediated tumor immunity becomes impaired when tumor cells interact with T cells via PD-L1 in the mouse tumor microenvironment. They showed that targeting PD-L1 or PD-1 with mAbs increased tumor cell lysis by T cells and suggested that tumor PD-L1 forms a “shield” preventing tumor cell lysis. Alongside other original mouse and human studies, this work generated scientific rationales for a new generation of cancer treatment focused on targeting the inhibitory PD-1/PD-L1 signaling pathway in the tumor microenvironment. See related article by Hirano and colleagues, Cancer Res 2005;65: 1089–96

Chronic inflammation and oncogenic pathway activation are key-contributing factors in colorectal cancer pathogenesis. However, colorectal intrinsic mechanisms linking these two factors in cancer development are poorly defined. Here, we show that intestinal epithelial cell (IEC)-specific deletion of Dot1l histone methyltransferase ( Dot1l ΔIEC ) reduced H3K79 dimethylation (H3K79me2) in IECs and inhibited intestinal tumor formation in Apc Min - and AOM-DSS-induced colorectal cancer models. IEC- Dot1l abrogation was accompanied by alleviative colorectal inflammation and reduced Wnt/β-catenin signaling activation. Mechanistically, Dot1l deficiency resulted in an increase in Foxp3 + RORϒ + regulatory T (Treg) cells and a decrease in inflammatory Th17 and Th22 cells, thereby reducing local inflammation in the intestinal tumor microenvironment. Furthermore, Dot1l deficiency caused a reduction of H3K79me2 occupancies in the promoters of the Wnt/β-catenin signaling genes, thereby diminishing Wnt/β-catenin oncogenic signaling pathway activation in colorectal cancer cells. Clinically, high levels of tumor H3K79me2 were detected in patients with colorectal carcinomas as compared to adenomas, and negatively correlated with RORϒ + FOXP3 + Treg cells. Altogether, we conclude that DOT1L is an intrinsic molecular node connecting chronic immune activation and oncogenic signaling pathways in colorectal cancer. Our work suggests that targeting the DOT1L pathway may control colorectal carcinogenesis. Significance : IEC-intrinsic DOT1L controls T cell subset balance and key oncogenic pathway activation, impacting colorectal carcinogenesis.

Background: Ovarian cancer (OC) is the most lethal malignancy of the female reproductive tract. Consequently, a better understanding of the malignant features in OC is pertinent. Mortalin (mtHsp70/GRP75/PBP74/HSPA9/HSPA9B) promotes cancer development, progression, metastasis, and recurrence. Yet, there is no parallel evaluation and clinical relevance of mortalin in the peripheral and local tumor ecosystem in OC patients. Methods: A cohort of 92 pretreatment women was recruited, including 50 OC patients, 14 patients with benign ovarian tumors, and 28 healthy women. Blood plasma and ascites fluid-soluble mortalin concentrations were measured by ELISA. Mortalin protein levels in tissues and OC cells were analyzed using proteomic datasets. The gene expression profile of mortalin in ovarian tissues was evaluated through the analysis of RNAseq data. Kaplan–Meier analysis was used to demonstrate the prognostic relevance of mortalin. Results: First, we found upregulation of local mortalin in two different ecosystems, i.e., ascites and tumor tissues in human OC compared to control groups. Second, abundance expression of local tumor mortalin is associated with cancer-driven signaling pathways and worse clinical outcome. Third, high mortalin level in tumor tissues, but not in the blood plasma or ascites fluid, predicts worse patient prognosis. Conclusions: Our findings demonstrate a previously unknown mortalin profile in peripheral and local tumor ecosystem and its clinical relevance in OC. These novel findings may serve clinicians and investigators in the development of biomarker-based targeted therapeutics and immunotherapies.