Immune Checkpoints and CAR-T Cells: The Pioneers in Future Cancer Therapies?

Although the ever-increasing number of cancer patients pose substantial challenges worldwide, finding a treatment with the highest response rate and the lowest number of side effects is still undergoing research. Compared to chemotherapy, the relatively low side effects of cancer immunotherapy have provided ample opportunity for immunotherapy to become a promising approach for patients with malignancy. However, the clinical translation of immune-based therapies requires robust anti-tumoral immune responses.

Novel HIV-1 miRNAs stimulate TNFα release in human macrophages via TLR8 signaling pathway.

Purpose: To determine whether HIV-1 produces microRNAs and elucidate whether these miRNAs can induce inflammatory response in macrophages (independent of the conventional miRNA function in RNA interference) leading to chronic immune activation.

Methods: Using sensitive quantitative Real Time RT-PCR and sequencing, we detected novel HIV-derived miRNAs in the sera of HIV+ persons, and associated with exosomes. Release of TNFα by macrophages challenged with HIV miRNAs was measured by ELISA.

Epigenetic regulation of tumor necrosis factor α (TNFα) release in human macrophages by HIV-1 single-stranded RNA (ssRNA) is dependent on TLR8 signaling.

Human macrophages at mucosal sites are essential targets for acute HIV infection. During the chronic phase of infection, they are persistent reservoirs for the AIDS virus. HIV virions gain entry into macrophages following ligation of surface CD4-CCR5 co-receptors, which leads to the release of two copies of HIV ssRNA.

Direct CD1d-mediated stimulation of APC IL-12 production and protective immune response to virus infection in vivo.

CD1d-restricted NKT cells rapidly stimulate innate and adaptive immunity through production of Th1 and/or Th2 cytokines and induction of CD1d(+) APC maturation. However, therapeutic exploitation of NKT cells has been hampered by their paucity and defects in human disease. NKT cell-APC interactions can be modeled by direct stimulation of human APCs through CD1d in vitro.

Circulating myeloid dendritic cells of advanced cancer patients result in reduced activation and a biased cytokine profile in invariant NKT cells.

CD1d-restricted invariant NKT (iNKT) cells play important regulatory roles in various immune responses, including antitumor immune responses. Previous studies have demonstrated quantitative and qualitative defects in iNKT cells of cancer patients, and these defects are clinically relevant as they are associated with poor prognosis. In this study we demonstrate that defects in the iNKT cell population can, at least in part, be attributed to defective interactions between iNKT cells and CD1d-expressing circulating myeloid dendritic cells (mDC), as mDC of patients with advanced melanoma and renal cell cancer reduced the activation and Th1 cytokine production of healthy donor-derived iNKT cells.

Effects of the administration of high-dose interleukin-2 on immunoregulatory cell subsets in patients with advanced melanoma and renal cell cancer.

Purpose: High-dose recombinant human interleukin-2 (IL-2) therapy is of clinical benefit in a subset of patients with advanced melanoma and renal cell cancer. Although IL-2 is well known as a T-cell growth factor, its potential in vivo effects on human immunoregulatory cell subsets are largely unexplored.

Experimental Design: Here, we studied the effects of high-dose IL-2 therapy on circulating dendritic cell subsets (DC), CD1d-reactive invariant natural killer T cells (iNKT), and CD4(+)CD25(+) regulatory-type T cells.

CD1d ligation on human monocytes directly signals rapid NF-kappaB activation and production of bioactive IL-12.

Natural killer T cells (NKT cells) expressing a semi-invariant CD1d-reactive T cell receptor (invariant NKT, iNKT) can be rapidly activated by monocytes or immature dendritic cells (iDCs) bearing a CD1d-presented glycolipid antigen and can in turn stimulate these myeloid cells to mature and produce IL-12. Previous studies have shown that iNKT-produced IFNgamma and CD40 ligand contribute to this dendritic cell maturation. This study demonstrates that CD1d ligation alone, in the absence of iNKT, could rapidly (within 24 h) stimulate production of bioactive IL-12p70 by CD1d+ human peripheral blood monocytes as well as iDCs.