Despite the clinical successes fostered by immune checkpoint inhibitors, mechanisms underlying PD-1 upregulation in tumor-infiltrating T cells remain an enigma. Here, we show that tumor-repopulating cells (TRCs) drive PD-1 upregulation in CD8 T cells through a transcellular kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) pathway. Interferon-γ produced by CD8 T cells stimulates release of high levels of Kyn produced by TRCs, which is transferred into adjacent CD8 T cells via the transporters SLC7A8 and PAT4. Kyn induces and activates AhR and thereby upregulates PD-1 expression. This Kyn-AhR pathway is confirmed in both tumor-bearing mice and cancer patients and its blockade enhances antitumor adoptive T cell therapy efficacy. Thus, we uncovered a mechanism of PD-1 upregulation with potential tumor immunotherapeutic applications.

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Identifying and sorting highly tumorigenic and metastatic tumor cells from a heterogeneous cell population is a daunting challenge. Here, we show that microfluidic devices can be used to sort marker‐based heterogeneous cancer stem cells (CSC) into mechanically stiff and soft subpopulations. The isolated soft tumor cells (< 400 Pa) but not the stiff ones (> 700 Pa) can form a tumor in immunocompetent mice with 100 cells per inoculation. Notably, only the soft, but not the stiff cells, isolated from CD133+, ALDH+, or side population CSCs, are able to form a tumor with only 100 cells in NOD‐SCID or immunocompetent mice. The Wnt signaling protein BCL9L is upregulated in soft tumor cells and regulates their stemness and tumorigenicity. Clinically, BCL9L expression is correlated with a worse prognosis. Our findings suggest that the intrinsic softness is a unique marker of highly tumorigenic and metastatic tumor cells.

Aim: Immunological checkpoint therapy is considered a powerful method for cancer therapy and acts by re-activating autologous T cells to kill the cancer cell. Myocarditis cases have been reported in cancer patients after immunological therapy; for example, nivolumab treatment is a monoclonal antibody that blocks programmed cell death-1/programmed cell death ligand-1 ligand interaction. This project provided insight into the inflammatory response as a benchmark to investigate the potential cardiotoxic effect of T cell response to the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis in regulating cardiomyocyte injury in vitro. Methods and Results: We investigated cardiomyopathy resulted from the PD-1/PD-L1 axis blockade using the anti-PD-1 antibody in Rockefeller University embryonic stem cells-derived cardiomyocytes (RUES2-CMs) and a melanoma tumor-bearing murine model. We found that nivolumab alone did not induce inflammatory-related proteins, including PD-L1 expression, and did not induce apoptosis, which was contrary to doxorubicin, a cardiotoxic chemotherapy drug. However, nivolumab was able to exacerbate the immune response by increasing cytokine and inflammatory gene expression in RUES2-CMs when co-cultured with CD4+ T lymphocytes and induced apoptosis. This effect was not observed when RUES2-CMs were co-cultured with CD8+ T lymphocytes. The in vivo model showed that the heart function of tumor-bearing mice was decreased after treatment with anti-PD-1 antibody and demonstrated a dilated left ventricle histological examination. The dilated left ventricle was associated with an infiltration of CD4+ and CD8+ T lymphocytes into the myocardium. PD-L1 and inflammatory-associated gene expression were significantly increased in anti-PD-1-treated tumor-bearing mice. Cleaved caspase-3 and mouse plasma cardiac troponin I expressions were increased significantly. Conclusion: PD-L1 expression on cardiomyocytes suppressed T-cell function. Blockade of PD-1 by nivolumab enhanced cardiomyocyte inflammation and apoptosis through the enhancement of T-cell response towards cardiomyocytes.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, however, genetic-environmental interactions and mechanisms associated with the development of HCC remains largely unclear. Our recent work described novel inactivating mutations of ARID2 (AT-rich interactive domain 2) in four major subtypes of HCC through exomic sequencing of ten HCV-associated HCCs and subsequent evaluation of the tumors from additional affected individuals. Here, we summarize the current knowledge about the relevance of ARID2 in HCC and the implication in future patient care.

Traumatic brain injury (TBI) causes increased release of several mediators from injured and dead cells and elicits microglial activation. Activated microglia change their morphology, migrate to injury sites, and release tumor necrosis factor-alpha (TNF-α) and others. In this study we used a controlled fluid percussion injury model of TBI in the rat to determine whether early (4 h post-injury) or late (4 days post-injury) treatment with MLC 601, a Traditional Chinese Medicine, would affect microglial activation and improve recovery. MLC 601 was chosen for this study because its herbal component MLC 901 was beneficial in treating TBI in rats. Herein, rats with induced TBI were treated with MLC 601 (0.2-0.8 mg/kg) 1 h (early treatment) or 4 day post-injury (late treatment) and then injected once daily for consecutive 2 days. Acute neurological and motor deficits were assessed in all rats the day before and 4 days after early MLC 601 treatment. An immunofluorescence microscopy method was used to count the numbers of the cells colocalized with neuron- and apoptosis-specific markers, and the cells colocalized with microglia- and TNF-α-specific markers, in the contused brain regions 4 days post-injury. An immunohistochemistry method was used to evaluate both the number and the morphological transformation of microglia in the injured areas. It was found that early treatment with MLC 601 had better effects in reducing TBI-induced cerebral contusion than did the late therapy with MLC 601. Cerebral contusion caused by TBI was associated with neurological motor deficits, brain apoptosis, and activated microglia (e.g., microgliosis, amoeboid microglia, and microglial overexpression of TNF-α), which all were significantly attenuated by MLC 601 therapy. Our data suggest that MLC 601 is a promising agent for treatment of TBI in rats.

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BackgroundTransducin β-like 1 X-linked receptor 1 (TBL1XR1) is an important transcriptional cofactor involved in the regulation of many signaling pathways, and is associated with carcinogenesis and tumor progression. However, the precise role of TBL1XR1 in these processes is not well understood.MethodsWe detected the expression of TBL1XR1 protein and mRNA in nasopharyngeal carcinoma (NPC) cell lines and biopsies by western blotting, real-time PCR and immunohistochemical staining (IHC). Overexpression of TBL1XR1 in NPC enhanced chemoresistance to cisplatin using two NPC cell lines in vitro and in vivo.ResultsTBL1XR1 was upregulated in NPC cell lines and clinical samples. The expression of TBL1XR1 was correlated with several clinicopathological factors including clinical stage, T classification, N classification and patient survival. Univariate and multivariate analysis revealed that TBL1XR1 was an independent prognostic factor for patient survival. In vitro and in vivo studies demonstrated that TBL1XR1 high expression induced resistance to cisplatin-induced apoptosis in NPC cells. Furthermore, we found that TBL1XR1 activated the NF-κB pathway and promoted transcription of genes downstream of NF-κB, especially anti-apoptotic genes.ConclusionsUpregulation of TBL1XR1 induces NPC cells resistance to cisplatin by activating the NF-κB pathway, and correlates with poor overall survival of NPC patients. TBL1XR1 has a pivotal role in NPC and could be a valuable prognostic factor as well as a novel biomarker for tailoring appropriate therapeutic regimes.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-195) contains supplementary material, which is available to authorized users.