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Blocking the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis could reverse the immune tolerance in the liver microenvironment of hepatocellular carcinoma (HCC). We investigated the efficacy and the safety of PD-1/PD-L1 inhibitors and the possibility of hepatitis B surface antigen (HBsAg) or hepatitis B virus (HBV) DNA levels as prognostic biomarkers in patients with HBV-related HCC. A retrospective study. We retrospectively analyzed patients with HBV-related HCC and positive quantitative HBsAg (qHBsAg) who received PD-1/PD-L1 inhibitor therapy at least once. The primary endpoints were overall survival (OS) and objective response rate (ORR), with the secondary endpoint being disease control rate (DCR). Cox regression models were used to illustrate the association of patient characteristics with survival. A total of 235 patients with HBV-related HCC were included in this study. The median OS for all patients was 20.9 months. The ORR and DCR were 15.7% and 70.6%, respectively. Baseline HBV DNA levels were associated with DCR (  = 0.004). Patients in the qHBsAg-response group in the fourth week had a longer OS after PD-1/PD-L1 inhibitor treatment compared to those in the qHBsAg nonresponse group (29.1 months vs 14.9 months,  = 0.04). Multivariate Cox regression analysis suggested that positive baseline HBV DNA (adjusted hazard ratio (aHR) = 2.6,  = 0.04) and qHBsAg nonresponse at week 4 after PD-1/PD-L1inhibitor therapy (aHR = 2.2,  = 0.04) were independent risk factors for survival. PD-1/PD-L1 inhibitor therapy in patients with HBV-related HCC showed better efficacy and safety. Negative HBV DNA and a short-term decline in qHBsAg from baseline were associated with superior survival prognosis.

Background A high baseline hepatitis B virus (HBV) load has always been listed as an exclusion criterion for programmed cell death-1 (PD-1) inhibitor-associated therapy in clinical trials, as the interaction between HBV load and anti-PD-1/PD-L1 therapy with anti HBV therapy remains controversial. Methods We retrospectively enrolled 70 unresectable HCC patients who were seropositive for HBsAg and accepted tenofovir alafenamide fumarate (TAF) therapy before anti-PD-1 in combination with an antiangiogenic treatment. Patients were divided into a low HBV DNA group (≤ 2000 IU/ml) and a high HBV DNA group (> 2000 IU/ml) according to the baseline HBV DNA levels. Tumour response and progression-free survival (PFS) were compared, and univariate and multivariate Cox analyses were performed to identify potential risk factors for PFS. The incidences of HBV reactivation and HBV-associated hepatitis were also recorded. Results 48 patients were assigned to the low group and the remaining 22 patients were assigned to the high group. The objective response rates (ORRs), disease control rates (DCRs), and PFS between the two groups showed no significant difference ( P  = 0.761, 0.552, and 0.784, respectively). The results of Cox analyses revealed that there was no relationship between baseline HBV load and PFS. Additionally, HBV reactivation occurred in only 2 patients (2.9%), and no patient experienced HBV-related hepatic impairment when given a continuous TAF treatment. Conclusions Baseline HBV loads do not affect the prognosis of HCC patients receiving anti-PD-1 in combination with an antiangiogenic therapy, while PD-1 inhibitors do not aggravate HBV reactivation and hepatic impairment in patients simultaneously subjected to TAF prophylaxis. Key points Baseline HBV loads do not affect the prognosis of HCC patients receiving anti-PD-1 in combination with antiangiogenic therapy. Besides, PD-1 inhibitors do not aggravate HBV reactivation and hepatic impairment undergoing concurrent TAF prophylaxis.

Background The poor prognosis of esophageal squamous cell carcinoma (ESCC) highlights the need for novel strategies against this disease. Our previous study suggested the involvement of CCL2 and tumor associated macrophages (TAMs) in esophageal carcinogenesis. Despite the recognition of TAMs as a promising target for cancer treatment, mechanisms underlying its infiltration, activation and tumor-promotive function in ESCC remain unknown. Methods Human esophageal tissue array and TCGA database were used to evaluate the clinical relevance of CCL2 and TAMs in ESCC. F344 rats and C57BL/6 mice were treated with N-nitrosomethylbenzylamine (NMBA) to establish orthotopic models of esophageal carcinogenesis. CCL2/CCR2 gene knockout mice and macrophage-specific PPARG gene knockout mice were respectively used to investigate the role of infiltration and polarization of TAMs in ESCC. CCL2-mediated monocyte chemotaxis was estimated in malignantly transformed Het-1A cells. THP-1 cells were used to simulate TAMs polarization in vitro. RNA-sequencing was performed to uncover the mechanism. Results Increasing expression of CCL2 correlated with TAMs accumulation in esophageal carcinogenesis, and they both predicts poor prognosis in ESCC cohort. Animal studies show blockade of CCL2-CCR2 axis strongly reduces tumor incidence by hindering TAMs recruitment and thereby potentiates the antitumor efficacy of CD8 + T cells in the tumor microenvironment. More importantly, M2 polarization increases PD-L2 expression in TAMs, resulting in immune evasion and tumor promotion through PD-1 signaling pathway. Conclusion This study highlights the role of CCL2-CCR2 axis in esophageal carcinogenesis. Our findings provide new insight into the mechanism of immune evasion mediated by TAMs in ESCC, suggesting the potential of TAMs-targeted strategies for ESCC prevention and immunotherapy.

Dysregulation of WNT/β-catenin is a hallmark of many cancer types and a key mediator of metastasis in solid tumors. Overactive β-catenin signaling hampers dendritic cell (DC) recruitment, promotes CD8 + T cell exclusion and increases the population of regulatory T cells (Tregs). The activity of WNT/β-catenin also induces the expression of programmed death-ligand 1 (PD-L1) on tumor cells and promotes programmed death-1 (PD-1) upregulation. Increased activity of WNT/β-catenin signaling after anti-PD-1 therapy is indicative of a possible implication of this signaling in bypassing immune checkpoint inhibitor (ICI) therapy. This review is aimed at giving a comprehensive overview of the WNT/β-catenin regulatory roles on PD-1/PD-L1 axis in tumor immune ecosystem, discussing about key mechanistic events contributed to the WNT/β-catenin-mediated bypass of ICI therapy, and representing inhibitors of this signaling as promising combinatory regimen to go with anti-PD-(L)1 in cancer immunotherapy. Ideas presented in this review imply the synergistic efficacy of such combination therapy in rendering durable anti-tumor immunity.

Immune checkpoint molecules are the antigen-independent generator of secondary signals that aid in maintaining the homeostasis of the immune system. The programmed death ligand-1 (PD-L1)/PD-1 axis is one among the most extensively studied immune-inhibitory checkpoint molecules, which delivers a negative signal for T cell activation by binding to the PD-1 receptor. The general attributes of PD-L1’s immune-suppressive qualities and novel mechanisms on the barrier functions of vascular endothelium to regulate blood vessel-related inflammatory diseases are concisely reviewed. Though targeting the PD-1/PD-L1 axis has received immense recognition—the Nobel Prize in clinical oncology was awarded in the year 2018 for this discovery—the use of therapeutic modulating strategies for the PD-L1/PD-1 pathway in chronic inflammatory blood vessel diseases is still limited to experimental models. However, studies using clinical specimens that support the role of PD-1 and PD-L1 in patients with underlying atherosclerosis are also detailed. Of note, delicate balances in the expression levels of PD-L1 that are needed to preserve T cell immunity and to curtail acute as well as chronic infections in underlying blood vessel diseases are discussed. A significant link exists between altered lipid and glucose metabolism in different cells and the expression of PD-1/PD-L1 molecules, and its possible implications on vascular inflammation are justified. This review summarizes the most recent insights concerning the role of the PD-L1/PD-1 axis in vascular inflammation and, in addition, provides an overview exploring the novel therapeutic approaches and challenges of manipulating these immune checkpoint proteins, PD-1 and PD-L1, for suppressing blood vessel inflammation.

Anti-PD-1-based therapy has resulted in a minimal clinical response in malignant gliomas. Gliomas contain numerous glioma-associated microglia/macrophages (GAMs), reported to contribute to an immunosuppressive microenvironment and promote glioma progression. However, whether and how GAMs affect anti-PD-1 immunotherapy in glioma remains unclear. Here, we demonstrated that M1-like GAMs contribute to the anti-PD-1 therapeutic response, while the accumulation of M2-like GAMs is associated with therapeutic resistance. Furthermore, we found that PD-L1 ablation reverses GAMs M2-like phenotype and is beneficial to anti-PD-1 therapy. We also demonstrated that tumor-induced impairment of the antigen-presenting function of GAMs could limit the antitumor immunity of CD4+ T cells in anti-PD-1 therapy. Our study highlights the impact of GAMs activation on anti-PD-1 treatment and provides new insights into the role of GAMs in regulating anti-PD-1 therapy in gliomas.

Programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade therapy has become a game-changing therapeutic approach revolutionizing the treatment setting of human malignancies, such as renal cell carcinoma (RCC). Despite the remarkable clinical activity of anti-PD-1 or anti-PD-L1 monoclonal antibodies, only a small portion of patients exhibit a positive response to PD-1/PD-L1 blockade therapy, and the primary or acquired resistance might ultimately favor cancer development in patients with clinical responses. In light of this, recent reports have signified that the addition of other therapeutic modalities to PD-1/PD-L1 blockade therapy might improve clinical responses in advanced RCC patients. Until, combination therapy with PD-1/PD-L1 blockade therapy plus cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitor (ipilimumab) or various vascular endothelial growth factor receptors (VEGFRs) inhibitors axitinib, such as axitinib and cabozantinib, has been approved by the United States Food and Drug Administration (FDA) as first-line treatment for metastatic RCC. In the present review, we have focused on the therapeutic benefits of the PD-1/PD-L1 blockade therapy as a single agent or in combination with other conventional or innovative targeted therapies in RCC patients. We also offer a glimpse into the well-determined prognostic factor associated with the clinical response of RCC patients to PD-1/PD-L1 blockade therapy.

Purpose of ReviewThis review summarizes recent data linking gut microbiota composition to ICI outcomes and gut microbiota-specific interventional clinical trials in melanoma.Recent FindingsPreclinical and clinical studies have demonstrated the effects of the gut microbiome modulation upon ICI response in advanced melanoma, with growing evidence supporting the ability of the gut microbiome to restore or improve ICI response in advanced melanoma through dietary fiber, probiotics, and FMT.SummaryImmune checkpoint inhibitors (ICI) targeting the PD-1, CTLA-4, and LAG-3 negative regulatory checkpoints have transformed the management of melanoma. ICIs are FDA-approved in advanced metastatic disease, stage III resected melanoma, and high-risk stage II melanoma and are being investigated more recently in the management of high-risk resectable melanoma in the peri-operative setting. The gut microbiome has emerged as an important tumor-extrinsic modulator of both response and immune-related adverse event (irAE) development in ICI-treated cancer in general, and melanoma in particular.

The expression of PD-L1 on tumor cells or within the tumor microenvironment has been associated with good prognosis and sustained clinical responses in immunotherapeutic regimens based on PD-L1/PD-1/CD80 immune checkpoint blockade. To look into the current controversy in cancer immunotherapy of the relative importance of PD-L1 expression on tumor cells versus non-tumor cells of the tumor microenvironment, a hematological mouse tumor model was chosen. By combining a genetic CRISPR/Cas9 and immunotherapeutic approach and using a syngeneic hematopoietic transplantable tumor model (E.G7-cOVA tumor cells), we demonstrated that dual blockade of PD-L1 interaction with PD-1 and CD80 enhanced anti-tumor immune responses that either delayed tumor growth or led to its complete eradication. PD-L1 expression on non-tumor cells of the tumor microenvironment was required for the promotion of tumor immune escape and its blockade elicited potent anti-tumor responses to PD-L1 WT and to PD-L1-deficient tumor cells. PD-L1+ tumors implanted in PD-L1-deficient mice exhibited delayed tumor growth independently of PD-L1 blockade. These findings emphasize that PD-L1 expression on non-tumor cells plays a major role in this tumor model. These observations should turn our attention to the tumor microenvironment in hematological malignancies because of its unappreciated contribution to create a conditioned niche for the tumor to grow and evade the anti-tumor immune response.

Immune checkpoint inhibitors (ICIs) confer remarkable therapeutic benefits to patients with various cancers. However, many patients are non-responders or develop resistance following an initial response to ICIs. There are no reliable biomarkers to predict the therapeutic effect of ICIs. Therefore, this study investigated the clinical implications of plasma levels of soluble anti-programmed death-1 (sPD-1) in patients with cancer treated with ICIs. In total, 22 patients (13 with non-small-cell lung carcinoma, 8 with gastric cancer, and 1 with bladder cancer) were evaluated for sPD-1 concentration using enzyme-linked immunosorbent assays for diagnostic and anti-PD-1 antibody analyses. sPD-1 levels were low before the administration of anti-PD-1 antibodies. After two and four cycles of anti-PD-1 antibody therapy, sPD-1 levels significantly increased compared with pretreatment levels (p = 0.0348 vs. 0.0232). We observed an increased rate of change in plasma sPD-1 concentrations after two and four cycles of anti-PD-1 antibody therapy that significantly correlated with tumor size progression (p = 0.024). sPD-1 may be involved in resistance to anti-PD-1 antibody therapy, suggesting that changes in sPD-1 levels can identify primary ICI non-responders early in treatment. Detailed analysis of each cancer type revealed the potential of sPD-1 as a predictive biomarker of response to ICI treatment in patients with cancer.