Tumor antigen-specific CD8+ T cells are negatively regulated by PD-1 and Tim-3 in human gastric cancer.

Cytotoxic CD8 T lymphocytes that are present in tumors and capable of recognizing tumor epitopes are nevertheless generally important in eliciting tumor rejection. NY-ESO-1 is a major target of CD8+ T cell recognition in gastric cancer (GC) and is among the most immunogenic tumor antigens defined to date. Thus, identifying the immune escape mechanisms responsible for inducing tumor-specific CD8+ T cell dysfunction may reveal effective strategies for immunotherapy. In an effort to understand in vivo tolerance mechanisms, we assessed the phenotype and function of NY-ESO-1-specific CD8+ T cells derived from peripheral blood lymphocytes (PBLs) and tumor-associated lymphocytes (TALs) of GC patients. Here, we report that Tim-3 expression defines a subpopulation of PD-1+ exhausted NY-ESO-1-specific CD8+ T cell and PD-1+Tim-3+ CD8+ T cells represented the largest subset of NY-ESO-1-specific CD8+ T cells in GC patients. Functionally, CD8+PD-1+Tim-3+ T cells were more impaired in IFN-γ, TNF-α and IL-2 production compared with PD-1+Tim-3- or PD-1-Tim-3- subsets. Dual blockade of Tim-3 and PD-1 during T-cell priming efficiently augmented proliferation and cytokine production by NY-ESO-1-specific CD8+ T cells could potentially be improved by therapeutic targeting of these inhibitory receptors, indicating that antitumor function of NY-ESO-1-specific CD8+ T cells could potentially be improved by therapeutic targeting of these inhibitory receptors.

Influences of Different Operative Methods on the Recurrence Rate of Non-Muscle-Invasive Bladder Cancer.

PURPOSE: To compare the influence of three operative approaches [transurethral en bloc resection of bladder tumor by pin-shaped electrode (pin-ERBT), transurethral resection of bladder tumor (TURBT) and transurethral holmium laser resection of bladder tumor (HoLRBT)] on the recurrence rate of non-muscle-invasive bladder cancer (NMIBC) at low dimension (i.e. diameter below 3 cm). MATERIALS AND METHODS: A retrospective analysis was conducted for a total of 115 patients affected by solitary NMIBC, with a diameter <3 cm, who were submitted to operation between March 2013 to May 2017. The patients were divided according to the operative method applied (pin-ERBT, TURBT and HoLRBT groups, respectively). The 2-year recurrence rate was compared among the three groups, and multivariat Cox hazard model analysis was applied to analyze the influencing factor(s) for postoperative recurrence. RESULTS: The 2-year recurrence rate was 10.0% in ERBT, 38.5% in TURBT and 40.0% in HoLRBT group, with a significant difference (P =0.014). According to the Cox hazard model analysis, age(HR=1.058, 95% CI: 1.019~1.098，P=0.003), operative method(HR=2.974,6.508, 95% CI: 0.862~10.255,1.657~25.566, P=0.023), smoking(HR=2.399, 95% CI: 1.147~5.017, P=0.020) and pathological grade(HR=2.012,95% CI: 1.279~3.165, P=0.002) were risk factors for postoperative recurrence of bladder cancer. CONCLUSION: Pin-ERBT can prominently decrease the postoperative recurrence rate of solitary NMIBC with a diameter <3 cm.

Circular RNA cir-ITCH Is a Potential Therapeutic Target for the Treatment of Castration-Resistant Prostate Cancer.

cir-ITCH, a well-known tumor-suppressive circular RNA, plays a critical role in different cancers. However, its expression and functional role in prostate cancer (PCa) are unclear. Herein, we explored the potential mechanism and tumor-inhibiting role of cir-ITCH in PCa. Using reverse transcriptase polymerase chain reaction assay, we analyzed the expression of cir-ITCH in PCa and paired adjacent nontumor tissue samples resected during surgical operation, as well as in two cell lines of human PCa (LNCaP and PC-3) and the immortalized normal prostate epithelial cell line (RWPE-1). Cell viability and migration of PCa cell lines were evaluated using CCK-8 and wound-healing assays. Expression of key proteins of the Wnt/ß-catenin and PI3K/AKT/mTOR pathways was detected using western blotting. We found that cir-ITCH expression was typically downregulated in the tissues and cell lines of PCa compared to that in the peritumoral tissue and in RWPE-1 cells, respectively. The results showed that cir-ITCH overexpression significantly inhibits the proliferation, migration, and invasion of human PCa cells and that reciprocal inhibition of expression occurred between cir-ITCH and miR-17. Proteins in the Wnt/ß-catenin and PI3K/AKT/mTOR pathways were downregulated by overexpression of cir-ITCH both in androgen receptor-positive LNCaP cells and androgen receptor-negative PC-3 cells. Taken together, these data demonstrated that cir-ITCH plays a tumor-suppressive role in human PCa cells, partly through the Wnt/ß-catenin and PI3K/AKT/mTOR pathways. Thus, cir-ITCH may serve as a novel therapeutic target for the treatment of PCa, especially castration-resistant prostate cancer.

Stable Intracerebral Transplantation of Neural Stem Cells for the Treatment of Paralysis Due to Ischemic Stroke.

NSI-566 is a stable, primary adherent neural stem cell line derived from a single human fetal spinal cord and expanded epigenetically with no genetic modification. This cell line is being tested in clinical trials in the U.S. for treatment of amyotrophic lateral sclerosis and spinal cord injury. In a single-site, phase I study, we evaluated the feasibility and safety of NSI-566 transplantation for the treatment of hemiparesis due to chronic motor stroke and determined the maximum tolerated dose for future trials. Three cohorts (n = 3 per cohort) were transplanted with one-time intracerebral injections of 1.2 × 107 , 2.4 × 107 , or 7.2 × 107 cells. Immunosuppression therapy with tacrolimus was maintained for 28 days. All subjects had sustained chronic motor strokes, verified by magnetic resonance imaging (MRI), initiated between 5 and 24 months prior to surgery with modified Rankin Scores [MRSs] of 2, 3, or 4 and Fugl-Meyer Motor Scores of 55 or less. At the 12-month visit, the mean Fugl-Meyer Motor Score (FMMS, total score of 100) for the nine participants showed 16 points of improvement (p = .0078), the mean MRS showed 0.8 points of improvement (p = .031), and the mean National Institutes of Health Stroke Scale showed 3.1 points of improvement (p = .020). For six participants who were followed up for 24 months, these mean changes remained stable. The treatment was well tolerated at all doses. Longitudinal MRI studies showed evidence indicating cavity-filling by new neural tissue formation in all nine patients. Although this was a small, one-arm study of feasibility, the results are encouraging to warrant further studies. Stem Cells Translational Medicine 2019;8:999-1007.

Targeting PD-1 and Tim-3 Pathways to Reverse CD8 T-Cell Exhaustion and Enhance Ex Vivo T-Cell Responses to Autologous Dendritic/Tumor Vaccines.

The paradoxical coexistence of spontaneous tumor antigen-specific immune response with progressive disease in cancer patients need to dissect the molecular pathways involved in tumor-induced T-cell dysfunction or exhaustion. Programmed cell death 1 (PD-1) has been identified as a marker of exhausted T cells in chronic disease states, and blockade of PD-1-PD-L1 interactions has been shown to partially restore T-cell function. We have found that T-cell immunoglobulin mucin (Tim) 3 is expressed on CD8+ tumor-infiltrating lymphocytes (TILs) isolated from patients with colorectal cancer. All T-cell immunoglobulin mucin 3 (Tim-3+) TILs coexpress PD-1, and Tim-3+ PD-1+ CD8+ TILs represent the predominant fraction of Tcells infiltrating tumors. Tim-3+PD-1+ CD8+ TILs exhibit the most severe exhausted phenotype as defined by failure to produce cytokines, such as interferon-γ, tumor necrosis factor-α, and interleukin-2. We further find that combined targeting of the Tim-3 and PD-1 pathways increased the frequencies of not only interferon-γ and tumor necrosis factor-α but also frequencies of proliferating tumor antigen-specific CD8+ T cells than targeting either pathway alone. A concomitant decrease in regulatory T cells and enhanced killing in a cytotoxicity assay was observed. Collectively, our findings support the use of Tim-3-Tim-3L blockade together with PD-1-PD-L1 blockade to reverse tumor-induced T-cell exhaustion/dysfunction in patients with colorectal cancer.