More than 10% of the world’s population is chronically infected with HIV, HCV or HBV, which cause severe disease and death. These viruses persist in part because continuous antigenic stimulation causes deterioration of virus-specific cytotoxic T lymphocyte (CTL) function and survival. Additionally, antiviral CTLs autonomously suppress their responses to limit immunopathology by upregulating inhibitory receptors such as Programmed cell death 1 (PD-1). Identification and blockade of the pathways that induce CTL dysfunction may facilitate clearance of chronic viral infections. We have identified that the prostaglandin E2 (PGE2) receptors EP2 and EP4 are upregulated on virus-specific CTLs during chronic LCMV infection and suppress CTL survival and function. We showed that the combined blockade of PGE2 and PD-1 signaling was therapeutic in terms of improving viral control and augmenting the numbers of functional virus-specific CTLs. Thus, PGE2 inhibition is both independent candidate therapeutic target and a promising adjunct therapy to PD-1 blockade for treatment of HIV and other chronic viral infections.

B-RafV600E inhibitors have been suggested to promote tumor regression with the help of host immunity, but this hypothesis has not been examined directly in detail. In this study, we profiled immunological changes in the tumor microenvironment and tumor infiltrating lymphocytes (TILs) in a B-RafV600E/Pten-driven murine model of melanoma, after administration of the BRafV600E small molecule inhibitor PLX4720. In this model, we found that as tumors developed they gradually acquired immunosuppressive features, including accumulation of regulatory T cells (Tregs) and CD11b+/Gr-1+ myeloid cells and loss of Th1 effector functions on CD4+ TILs, such as CD40L and IFN-γ expression. PLX4720 administration promoted development of a more immune stimulatory microenvironment associated with a relative increase in CD40L and IFNγ expression on intratumoral CD4+ TILs and a reduced accumulation of Tregs and CD11b+/Gr-1+ myeloid cells. Strikingly, CD40L or IFNγ blockade compromised the ability of PLX4720 to inhibit melanoma growth. Supporting this result, agonistic CD40 antibody was sufficient to evoke anti-tumor immunity and suppress tumor growth in tumor-bearing mice. Taken together, our results establish the critical role of immune-related changes with key contributions for CD40L and IFNγ signaling in the anti-tumor responses triggered in vivo by BRafV600E inhibitors.

Mobilization and translation of mRNAs, two important events believed to involve stress granules (SGs), in neurons are important for their survival and activities. However, the formation and disassembly of SGs in neurons remains unclear. By using an arsenite-induced neuronal stress model of primary spinal cord neuron cultures, we demonstrate the formation of SGs that contain common SG components and RNAs in both stressed neuronal cell bodies and their neurites. By employing siRNA knockdown, we discovered that dynein motor subunit localizes in SG, and is important for SG assembly in neurons. Under stress, dynein motor subunit also facilitates translational repression and enhances the formation and integrity of SG in neurons. By blocking the energy source of dynein motor, both the formation and disassembly of SG are attenuated. These findings demonstrate, for the first time, that dynein motor complex plays a critical role in the dynamics of neuronal SGs, as well as translation of certain mRNAs.

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