Stem cell like memory T (T_SCM) cells have emerged as the apex of memory T cell differentiation for their properties of self-renewal and replenishing progenies. With potent long-term persistence, proliferative capacity and antitumor activity, T_SCM cells were thought to be the ideal candidate for cancer immunotherapies. Several strategies have been proposed, such as manipulations of cytokines, metabolic factors, signal pathways, and T cell receptor signal intensity, to induce more T_SCM cells in vitro, in the hope that they could reach a clinical order of magnitude to provide more long-lasting and effective anti-tumor effects in vivo. In this review, we summarized the differentiation characteristics of T_SCM cells and strategies to generate more T_SCM cells. We focused on their roles and application in the cancer immunotherapy especially in adoptive cell transfer therapy and cancer therapeutic vaccines, and hopefully provided clues for future understanding and researches.

As the primary glial cells in the peripheral nervous system (PNS), Schwann cells (SCs) have been proven to influence the behavior of cancer cells profoundly and are involved in cancer progression through extensive interactions with cancer cells and other stromal cells. Indeed, the tumor microenvironment (TME) is a critical factor that can significantly limit the efficacy of immunotherapeutic approaches. The TME promotes tumor progression in part by reshaping an immunosuppressive state. The immunosuppressive TME is the result of the crosstalk between the tumor cells and the different immune cell subsets, including macrophages, natural killer (NK) cells, dendritic cells (DCs), lymphocytes, myeloid-derived suppressor cells (MDSCs), etc. They are closely related to the anti-tumor immune status and the clinical prognosis of cancer patients. Increasing research demonstrates that SCs influence these immune cells and reshape the formation of the immunosuppressive TME via the secretion of various cytokines, chemokines, and other effector molecules, eventually facilitating immune evasion and tumor progression. In this review, we summarize the SC reprogramming in TME, the emerging role of SCs in tumor immune microenvironment, and the underlying mechanisms involved. We also discuss the possible therapeutic strategies to selectively target SCs, providing insights and perspectives for future research and clinical studies involving SC-targeted treatment.

Original Article Bidirectional regulation between tumor cell-intrinsic PD-L1 and TGF-β1 in epithelial-to-mesenchymal transition in melanoma Zhen Li, Fengdi Wang, Jianzhong Dang, Fanjun Cheng, Fang Zheng

Previous work from our laboratory has confirmed that human ether-à-go-go-related gene 1 (hERG1) K(+) channels are constitutively expressed in leukemia cells and enhanced cell proliferation. More importantly, it has shown that stromal cell-derived factor-1a (SDF-1a) significantly increases hERG1 K(+) tail current and a specific hERG1 K(+) channels inhibitor significantly blocks SDF-1a-induced migration of leukemic cells. In this study, we investigated a possible regulatory effect of hERG1 K(+) channels upon SDF-1a-mediated cell proliferation as a mean to uncover new molecular events involved in bone marrow microenvironment and leukemogenesis. RT-PCR showed that SDF-1a enhanced hERG1 expression in a dose-dependent manner. Cell proliferation assay illustrated that SDF-1a promoted cell proliferation in a dose-dependent manner, whereas this effect was impaired by E-4031. In addition, E-4031 inhibited SDF-1a-stimulated leukemic cell proliferation by inducing G(0)/G(1) arrest. Interestingly, E-4031 promoted SDF-1a-induced apoptosis in HL-60 and leukemic blasts, which markedly impaired the protection effect of SDF-1a in AML. Moreover, SDF-1a increased the expression of Wnt/beta-catenin target genes, including beta-catenin, cyclin-D1, and c-myc; however, this manner was abolished by blockage with the hERG1 K(+) channels. Taken together, our results provide evidence of a novel mechanism involved in the proliferative effects of SDF-1a and highlight hERG1 K(+) channels as a therapeutic target for leukemia treatment and prevention.

Recent studies have indicated that therapeutic antibodies targeting PD-L1 show remarkable efficacy in clinical trials in multiple tumors and that a melanoma cell-intrinsic PD-1: PD-L1 axis promotes tumor growth. However, few studies have shown tumor-intrinsic PD-L1 effects in malignant melanoma initiating cells (MMICs). Here, we aim to determine the possible regulatory effects of PD-L1 on MMICs. The ALDEFLUOR kit was used to identify ALDH⁺ MMICs. Flow cytometry was used to examine the expression of PD-L1 on ALDH⁺ MMICs. To determine the role of PD-L1 in MMICs self-renewal, we cultured melanoma cells with anti-PD-L1 and measured tumorsphere formation and apoptosis. In addition, the effects of anti-PD-L1 on tumorigenicity and residual ALDH⁺ MMICs in tumors were evaluated in vivo. We demonstrated that melanoma cell-intrinsic PD-L1 was expressed in ALDH⁺ MMICs. Blocking PD-L1 in melanoma cell lines impaired tumorsphere formation and induced the apoptosis of sphere cells. In addition, blocking PD-L1 inhibited tumor growth in vivo. We observed residual ALDH⁺ MMICs within the tumor. The results showed that blocking PD-L1 also significantly decreased the residual ALDH⁺ MMICs in the tumors. In conclusion, these results suggest a new mechanism underlying melanoma progression and PD-L1-targeted therapy, which is distinct from the immunomodulatory actions of PD-L1.