Explore the vast range of titles available.

Spermatogenesis is a cyclical process in which different generations of spermatids undergo a series of developmental steps at a fixed time and finally produce spermatids. Here, we report that overexpression of PD‐L1 (B7 homolog1) in the testis causes sperm developmental disorders and infertility in male mice, with severe malformation and sloughing during spermatid development, characterized by disorganized and collapsed seminiferous epithelium structure. PD‐L1 needs to be simultaneously expressed on Sertoli cells and spermatogonia to cause spermatogenesis failure. After that, we excluded the influence of factors such as the PD‐L1 receptor and humoral regulation, confirming that PD‐L1 has an intrinsic function to interact with PD‐L1. Studies have shown that PD‐L1 not only serves as a ligand but also plays a receptor‐like role in signal transduction. PD‐L1 interacts with PD‐L1 to affect the adhesive function of germ cells, causing malformation and spermatid sloughing. Taken together, these results indicate that PD‐L1 can interact with PD‐L1 to cause germ cell detachment and male infertility.

Cancer immunotherapy involves blocking the interactions between the PD-1/PD-L1 immune checkpoints with antibodies. This has shown unprecedented positive outcomes in clinics. Particularly, the PD-L1 antibody therapy has shown the efficiency in blocking membrane PD-L1 and efficacy in treating some advanced carcinoma. However, this therapy has limited effects on many solid tumors, suspecting to be relevant to PD-L1 located in other cellular compartments, where they play additional roles and are associated with poor prognosis. In this review, we highlight the advances of 3 current strategies on PD-1/PD-L1 based immunotherapy, summarize cellular distribution of PD-L1, and review the versatile functions of intracellular PD-L1. The intracellular distribution and function of PD-L1 may indicate why not all antibody blockade is able to fully stop PD-L1 biological functions and effectively inhibit tumor growth. In this regard, gene silencing may have advantages over antibody blockade on suppression of PD-L1 sources and functions. Apart from cancer cells, PD-L1 silencing on host immune cells such as APC and DC can also enhance T cell immunity, leading to tumor clearance. Moreover, the molecular regulation of PD-L1 expression in cells is being elucidated, which helps identify potential therapeutic molecules to target PD-L1 production and improve clinical outcomes. Based on our understandings of PD-L1 distribution, regulation, and function, we prospect that the more effective PD-L1-based cancer immunotherapy will be combination therapies.

T cell‐derived small extracellular vesicles (sEVs) exhibit anti‐cancer effects. However, their anti‐cancer potential should be reinforced to enhance clinical applicability. Herein, we generated interleukin‐2‐tethered sEVs (IL2‐sEVs) from engineered Jurkat T cells expressing IL2 at the plasma membrane via a flexible linker to induce an autocrine effect. IL2‐sEVs increased the anti‐cancer ability of CD8+ T cells without affecting regulatory T (Treg) cells and down‐regulated cellular and exosomal PD‐L1 expression in melanoma cells, causing their increased sensitivity to CD8+ T cell‐mediated cytotoxicity. Its effect on CD8+ T and melanoma cells was mediated by several IL2‐sEV‐resident microRNAs (miRNAs), whose expressions were upregulated by the autocrine effects of IL2. Among the miRNAs, miR‐181a‐3p and miR‐223‐3p notably reduced the PD‐L1 protein levels in melanoma cells. Interestingly, miR‐181a‐3p increased the activity of CD8+ T cells while suppressing Treg cell activity. IL2‐sEVs inhibited tumour progression in melanoma‐bearing immunocompetent mice, but not in immunodeficient mice. The combination of IL2‐sEVs and existing anti‐cancer drugs significantly improved anti‐cancer efficacy by decreasing PD‐L1 expression in vivo. Thus, IL2‐sEVs are potential cancer immunotherapeutic agents that regulate both immune and cancer cells by reprogramming miRNA levels.

Background An elevated Neutrophil-to-lymphocyte ratio (NLR) is associated with worse outcomes in several malignancies. However, its role with contemporary immune checkpoint blockade (ICB) is unknown. We investigated the utility of NLR in metastatic renal cell carcinoma (mRCC) patients treated with PD-1/PD-L1 ICB. Methods We examined NLR at baseline and 6 (±2) weeks later in 142 patients treated between 2009 and 2017 at Dana-Farber Cancer Institute (Boston, USA). Landmark analysis at 6 weeks was conducted to explore the prognostic value of relative NLR change on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Cox and logistic regression models allowed for adjustment of line of therapy, number of IMDC risk factors, histology and baseline NLR. Results Median follow up was 16.6 months (range: 0.7–67.8). Median duration on therapy was 5.1 months (<1–61.4). IMDC risk groups were: 18% favorable, 60% intermediate, 23% poor-risk. Forty-four percent were on first-line ICB and 56% on 2nd line or more. Median NLR was 3.9 (1.3–42.4) at baseline and 4.1 (1.1–96.4) at week 6. Patients with a higher baseline NLR showed a trend toward lower ORR, shorter PFS, and shorter OS. Higher NLR at 6 weeks was a significantly stronger predictor of all three outcomes than baseline NLR. Relative NLR change by ≥25% from baseline to 6 weeks after ICB therapy was associated with reduced ORR and an independent prognostic factor for PFS ( p  < 0.001) and OS ( p  = 0.004), whereas a decrease in NLR by ≥25% was associated with improved outcomes. Conclusions Early decline and NLR at 6 weeks are associated with significantly improved outcomes in mRCC patients treated with ICB. The prognostic value of the readily-available NLR warrants larger, prospective validation.

Cancer is now considered a tumor microenvironment (TME) disease, although it was originally thought to be a cell and gene expression disorder. Over the past 20 years, significant advances have been made in understanding the complexity of the TME and its impact on responses to various anticancer therapies, including immunotherapies. Cancer immunotherapy can recognize and kill cancer cells by regulating the body's immune system. It has achieved good therapeutic effects in various solid tumors and hematological malignancies. Recently, blocking of programmed death‐1 (PD‐1), programmed death‐1 ligand‐1 (PD‐L1), and programmed death Ligand‐2 (PD‐L2), the construction of antigen chimeric T cells (CAR‐T) and tumor vaccines have become popular immunotherapies Tumorigenesis, progression, and metastasis are closely related to TME. Therefore, we review the characteristics of various cells and molecules in the TME, the interaction between PD‐1 and TME, and promising cancer immunotherapy therapeutics. In the past decades, the treatment methods for tumors have been changing rapidly. Traditional treatment methods, such as radiotherapy and chemotherapy regimens, have gradually revealed their shortcomings. As scientists continue to study the tumor microenvironment, new cellular properties, and immune checkpoints regarding TME are being discovered, and immunotherapy based on monoclonal antibodies, engineered cells, tumor vaccines, and other technologies have shown good therapeutic effects and lower risks. This review presents the latest research about TME and the latest progress in immunotherapy.

Background Metastatic castration‐resistant prostate cancer (mCRPC) remains fatal and incurable, despite a variety of treatments that can delay disease progression and prolong life. Immune checkpoint therapy is a promising treatment. However, emerging evidence suggests that exosomal programmed necrosis ligand 1 (PD‐L1) directly binds to PD‐1 on the surface of T cells in the drain lineage lymph nodes or neutralizes administered PD‐L1 antibodies, resulting in poor response to anti‐PD‐L1 therapy in mCRPC. Materials and Methods Western blotting and immunofluorescence were performed to compare PD‐L1 levels in exosomes derived from different prostate cancer cells. PC3 cells were subcutaneously injected into nude mice, and then ELISA assay was used to detect human specific PD‐L1 in exosomes purified from mouse serum. The function of CD8+ T cells was detected by T cell mediated tumor cell killing assay and FACS analysis. A subcutaneous xenograft model was established using mouse prostate cancer cell RM1, exosomes with or without PD‐L1 were injected every 3 days, and then tumor size and weight were analyzed to evaluate the effect of exosomal PD‐L1. Results Herein, we found that exosomal‐PD‐L1 was taken up by tumor cells expressing low levels of PD‐L1, thereby protecting them from T‐cell killing. Higher levels of PD‐L1 were detected in exosomes derived from the highly malignant prostate cancer PC3 and DU145 cell lines. Moreover, exosomal PD‐L1 was taken up by the PD‐L1‐low‐expressing LNCaP cell line and inhibited the killing function of CD8‐T cells on tumor cells. The growth rate of RM1‐derived subcutaneous tumors was decreased after knockdown of PD‐L1 in tumor cells, whereas the growth rate recovered following exosomal PD‐L1 tail vein injection. Furthermore, in the serum of mice with PCa subcutaneous tumors, PD‐L1 was mainly present on exosomes. Conclusion In summary, tumor cells share PD‐L1 synergistically against T cells through exosomes. Inhibition of exosome secretion or prevention of PD‐L1 sorting into exosomes may improve the therapeutic response of prostate tumors to anti‐PD‐L1 therapy.

Purpose A same-day PET imaging agent capable of measuring PD-L1 status in tumors is an important tool for optimizing PD-1 and PD-L1 treatments. Herein we describe the discovery and evaluation of a novel, fluorine-18 labeled macrocyclic peptide-based PET ligand for imaging PD-L1. Methods [ 18 F]BMS-986229 was synthesized via copper mediated click-chemistry to yield a PD-L1 PET ligand with picomolar affinity and was tested as an in-vivo tool for assessing PD-L1 expression. Results Autoradiography showed an 8:1 binding ratio in L2987 (PD-L1 (+)) vs. HT-29 (PD-L1 (-)) tumor tissues, with >90% specific binding. Specific radioligand binding (>90%) was observed in human non-small-cell lung cancer (NSCLC) and cynomolgus monkey spleen tissues. Images of PD-L1 (+) tissues in primates were characterized by high signal-to-noise, with low background signal in non-expressing tissues. PET imaging enabled clear visualization of PD-L1 expression in a murine model in vivo, with 5-fold higher uptake in L2987 (PD-L1 (+)) than in control HT-29 (PD-L1 (-)) tumors. Moreover, this imaging agent was used to measure target engagement of PD-L1 inhibitors (peptide or mAb), in PD-L1 (+) tumors as high as 97%. Conclusion A novel 18 F-labeled macrocyclic peptide radioligand was developed for PET imaging of PD-L1 expressing tissues that demonstrated several advantages within a nonhuman primate model when compared directly to adnectin- or mAb-based ligands. Clinical studies are currently evaluating [ 18 F]BMS-986229 to measure PD-L1 expression in tumors.

The majority of lung cancer patients progressing from conventional therapies are refractory to PD‐L1/PD‐1 blockade monotherapy. Here, we show that baseline systemic CD4 immunity is a differential factor for clinical responses. Patients with functional systemic CD4 T cells included all objective responders and could be identified before the start of therapy by having a high proportion of memory CD4 T cells. In these patients, CD4 T cells possessed significant proliferative capacities, low co‐expression of PD‐1/LAG‐3 and were responsive to PD‐1 blockade ex vivo and in vivo . In contrast, patients with dysfunctional systemic CD4 immunity did not respond even though they had lung cancer‐specific T cells. Although proficient in cytokine production, CD4 T cells in these patients proliferated very poorly, strongly co‐upregulated PD‐1/LAG‐3, and were largely refractory to PD‐1 monoblockade. CD8 immunity only recovered in patients with functional CD4 immunity. T‐cell proliferative dysfunctionality could be reverted by PD‐1/LAG‐3 co‐blockade. Patients with functional CD4 immunity and PD‐L1 tumor positivity exhibited response rates of 70%, highlighting the contribution of CD4 immunity for efficacious PD‐L1/PD‐1 blockade therapy. Synopsis Lung cancer patients are often refractory to PD‐L1/PD‐1 blockade therapy. This study shows that patients progressing from conventional therapies that have functional CD4 T cells respond to PD‐L1/PD‐1 blockade immunotherapy, while patients with proliferative dysfunctional CD4 T cells do not respond. Functional systemic CD4 immunity is required for objective clinical responses to PD‐L1/PD‐1 blockade therapy in human lung cancer patients. Systemic memory CD4 T cells identify intrinsic non‐responder from potentially responder patients. 70% of patients with high baseline percentages of memory CD4 T cells and PD‐L1‐positive tumors respond to therapy. Proliferative CD4 dysfunctionality in non‐responder patients can be overcome by PD‐1/LAG‐3 co‐blockade. Graphical Abstract Lung cancer patients are often refractory to PD‐L1/PD‐1 blockade therapy. This study shows that patients progressing from conventional therapies that have functional CD4 T cells respond to PD‐L1/PD‐1 blockade immunotherapy, while patients with proliferative dysfunctional CD4 T cells do not respond.

Despite multidisciplinary treatment for patients with advanced gastric cancer, their prognosis remains poor. Therefore, the development of novel therapeutic strategies is urgently needed, and immunotherapy utilizing anti‐programmed death 1/‐programmed death ligand‐1 mAb is an attractive approach. However, as there is limited information on how programmed death ligand‐1 is upregulated on tumor cells within the tumor microenvironment, we examined the mechanism of programmed death ligand‐1 regulation with a particular focus on interferon gamma in an in vitro setting and in clinical samples. Our in vitro findings showed that interferon gamma upregulated programmed death ligand‐1 expression on solid tumor cells through the JAK‐signal transducer and activator of transcription pathway, and impaired the cytotoxicity of tumor antigen‐specific CTL against tumor cells. Following treatment of cells with anti‐programmed death ligand‐1 mAb after interferon gamma‐pre‐treatment, the reduced anti‐tumor CTL activity by interferon gamma reached a higher level than the non‐treatment control targets. In contrast, programmed death ligand‐1 expression on tumor cells also significantly correlated with epithelial‐mesenchymal transition phenotype in a panel of solid tumor cells. In clinical gastric cancer samples, tumor membrane programmed death ligand‐1 expression significantly positively correlated with the presence of CD8‐positive T cells in the stroma and interferon gamma expression in the tumor. The results suggest that gastric cancer patients with high CD8‐positive T‐cell infiltration may be more responsive to anti‐programmed death 1/‐programmed death ligand‐1 mAb therapy. PD‐L1 levels significantly correlated with CD8 (stroma) levels (P = .018), but not with CD3 nor CD4 in tumor/stroma in gastric cancer. Furthermore, PD‐L1 levels also significantly positively correlated with tumor IFN‐γ levels. The results suggests that upregulation of PD‐L1 may result from increased IFN‐γ production by CTLs which migrate to the tumor during immune activation.

The immune checkpoint pathway consisting of the cell membrane-bound molecule programmed death protein 1 (PD-1) and its ligand PD-L1 has been found to mediate negative regulatory signals that effectively inhibit T-cell proliferation and function and impair antitumor immune responses. Considerable evidence suggests that the PD-1/PD-L1 pathway is responsible for tumor immune tolerance and immune escape. Blockage of this pathway has been found to reverse T lymphocyte depletion and restore antitumor immunity. Antagonists targeting this pathway have shown significant clinical activity in specific cancer types. Although originally identified as membrane-type molecules, several other forms of PD-1/PD-L1 have been detected in the blood of cancer patients, including soluble PD-1/PD-L1 (sPD-1/sPD-L1) and exosomal PD-L1 (exoPD-L1), increasing the composition and functional complications of the PD-1/PD-L1 signaling pathway. For example, sPD-1 has been shown to block the PD-1/PD-L immunosuppressive pathway by binding to PD-L1 and PD-L2, whereas the role of sPD-L1 and its mechanism of action in cancer remain unclear. In addition, many studies have investigated the roles of exoPD-L1 in immunosuppression, as a biomarker for tumor progression and as a predictive biomarker for response to immunotherapy. This review describes the molecular mechanisms underlying the generation of sPD-1/sPD-L1 and exoPD-L1, along with their biological activities and methods of detection. In addition, this review discusses the clinical importance of sPD-1/sPD-L1 and exoPD-L1 in cancer, including their predictive and prognostic roles and the effects of treatments that target these molecules.