Prediction of biomarkers and therapeutic combinations for anti-PD-1 immunotherapy using the global gene network association.
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ABSTRACT:
SUBMITTER: Wu CC
PROVIDER: S-EPMC8748689 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Programmed cell death 1 (PD-1)/programmed cell death 1 ligand (PD-L1) blockade has shown promising effects in cancer immunotherapy. Removing the so-called " brakes" on T cell immune responses by blocking the PD-1/PD-L1 check point should boost anti-tumor immunity and provide durable tumor regression for cancer patients. However, 30%-60% of patients show no response to PD-1/PD-L1 blockade. Thus, it is urgent to explore the underlying resistance mechanisms to improve sensitivity to anti-PD-1/PD-L1 therapy. We propose that the mechanisms promoting resistance mainly include T cell exclusion or exhaustion at the tumor site, immunosuppressive factors in the tumor microenvironment (TME), and a range of tumor-intrinsic factors. This review highlights the power of studying the cellular and molecular mechanisms of resistance to improve the rational design of combination therapeutic strategies that can be translated to the clinic. Here, we briefly discuss the development of PD-1/PD-L1 blockade agents and focus on the current issues and future prospects for potential combinatorial therapeutic strategies that include anti-PD-1/PD-L1 therapy, based upon the available preclinical and clinical data.
| S-EPMC5953954 | biostudies-literature
Project description:BackgroundAnti-PD-1 immunotherapies have shown clinical benefit in multiple cancers, but response was only observed in a subset of patients. Predicting which patients will respond is an urgent clinical need, but current companion diagnosis based on PD-L1 IHC staining shows limited predictability.MethodsA dynamic, metrics-based biomarker was developed to discriminate responders from non-responders for anti-PD-1 immunotherapy in B16F10 melanoma-bearing mice.ResultsSimilar to patients, there was considerable heterogeneity in response to anti-PD-1 immunotherapy in mice. Compared with the control group, 45% of anti-PD-1 antibody-treated mice displayed improved survival (defined as responders) and the remainder only gained little, if any, survival benefit from PD-1 blockade (non-responders). Interestingly, the dynamics of IFN-γ secretion by peripheral lymphocytes was associated with faster secretion onset (shorter lag time), stronger exponential phase, shorter time to half magnitude, and higher magnitude of secretion in responders at day 10 after tumour inoculation. To sufficiently predict responders from non-responders, IFN-γ secretion descriptors as well as phenotypic markers were subjected to multivariate analysis using orthogonal partial least-squares discriminant analysis (OPLS-DA).ConclusionsBy integrating phenotypic markers, IFN-γ secretion descriptors sufficiently predict response to anti-PD-1 immunotherapy. Such a dynamic, metrics-based biomarker holds high diagnostic potential for anti-PD-1 checkpoint immunotherapy.
| S-EPMC6353899 | biostudies-literature
Project description:In recent years, anti-PD-1/anti-PD-L1 has been considered to be a valuable therapeutic target and prognostic indicator for triple-negative breast cancer. We analyzed all publications published in the field from their inception until the present day in order to determine the current research status and hotspots. All related publications were searched on the Web of Science. Our research used R-studio (bibliometrix package), VOSviewer, and CiteSpace to analyze and obtain annual publications and citation information, articles, highest publication countries and affiliations, influential journals and authors, keyword analysis, and keyword bursts. In total, 851 documents were retrieved including 628 articles and 223 review articles. The output of publications increased year by year from 2013 to 2021. However, the average article citation times reached the top in 2014 but generally showed a downward trend from 2014 to 2021. It was an article written by Schmid et al. in 2018 that received the most citations. With regard to publications, citations, and link strength, among the top countries was the United States. Cancers was the most published journal. Schmid and Loi ranked top in total citations and h-index. Schmid has the largest M-index and Loi has the most publication. The keywords that received the most attention were "Immunotherapy", "PD-L1", "Triple-negative breast cancer", "Tumor-infiltrating lymphocytes", and "Expression". According to the report, this current research focuses on immunotherapy for triple-negative breast cancer and the expression of PD-L1 and tumor-infiltrating lymphocytes (TILs). Pembrolizumab and Atezolizumab plus chemotherapy have completed the Phase 3 clinical trial. However, the biomarkers were limited in predicting the treatment prognosis. Through the scientometric analysis, we can understand the current research status and potential research points in this filed and provide research direction for researchers.
| S-EPMC9875294 | biostudies-literature
Project description:BackgroundThe therapeutic effect of immune checkpoint blockers, especially the neutralizing antibodies of programmed cell death (PD-1) and its ligand programmed death ligand 1 (PD-L1), has been well verified in melanoma. Nevertheless, the dissatisfactory response rate and the occurrence of resistance significantly hinder the treatment effect. Inflammation-related molecules like A20 are greatly implicated in cancer immune response, but the role of tumorous A20 in antitumor immunity and immunotherapy efficacy remains elusive.MethodsThe association between tumorous A20 expression and the effect of anti-PD-1 immunotherapy was determined by immunoblotting, immunofluorescence staining and flow cytometry analysis of primary tumor specimens from melanoma patients. Preclinical mouse model, in vitro coculture system, immunohistochemical staining and flow cytometry analysis were employed to investigate the role of A20 in regulating the effect of anti-PD-1 immunotherapy. Bioinformatics, mass spectrum analysis and a set of biochemical analyzes were used to figure out the underlying mechanism.ResultsWe first discovered that upregulated A20 was associated with impaired antitumor capacity of CD8+T cells and poor response to anti-PD-1 immunotherapy in melanoma patients. Subsequent functional studies in preclinical mouse model and in vitro coculture system proved that targeting tumorous A20 prominently improved the effect of immunotherapy through the invigoration of infiltrating CD8+T cells via the regulation of PD-L1. Mechanistically, A20 facilitated the ubiquitination and degradation of prohibitin to potentiate STAT3 activation and PD-L1 expression. Moreover, tumorous A20 expression was highly associated with the ratio of Ki-67 percentage in circulating PD-1+CD8+T cells to tumor burden.ConclusionsTogether, our findings uncover a novel crosstalk between inflammatory molecules and antitumor immunity in melanoma, and highlight that A20 can be exploited as a promising target to bring clinical benefit to melanomas refractory to immune checkpoint blockade.
| S-EPMC7733187 | biostudies-literature
Project description:Simple Summary Although immune checkpoint blockade has yielded unprecedented and durable responses in cancer patients, the efficacy of this treatment remains limited. Radiation therapy can induce immunogenic cell death that contributes to the local efficacy of irradiation. However, radiation-induced systemic responses are scarce. Studies combining radiation with checkpoint inhibitors suggest a synergistic potential of this strategy. In this review, we focused on parameters that can be optimized to enhance the anti-tumor immune response that results from this association, in order to achieve data on dose, fractionation, target volume, lymph nodes sparing, radiation particles, and other immunomodulatory agents. These factors should be considered in future trials for better clinical outcomes. To this end, we discussed the main preclinical and clinical data available to optimize the efficacy of the treatment combination. Abstract Immune checkpoint inhibitors have been associated with long-term complete responses leading to improved overall survival in several cancer types. However, these novel immunotherapies are only effective in a small proportion of patients, and therapeutic resistance represents a major limitation in clinical practice. As with chemotherapy, there is substantial evidence that radiation therapy promotes anti-tumor immune responses that can enhance systemic responses to immune checkpoint inhibitors. In this review, we discuss the main preclinical and clinical evidence on strategies that can lead to an enhanced response to PD-1/PD-L1 blockade in combination with radiation therapy. We focused on central issues in optimizing radiation therapy, such as the optimal dose and fractionation for improving the therapeutic ratio, as well as the impact on immune and clinical responses of dose rate, target volume, lymph nodes irradiation, and type of radiation particle. We explored the addition of a third immunomodulatory agent to the combination such as other checkpoint inhibitors, chemotherapy, and treatment targeting the tumor microenvironment components. The strategies described in this review provide a lead for future clinical trials.
| S-EPMC8508444 | biostudies-literature
Project description:Drug combinations, offering increased therapeutic efficacy and reduced toxicity, play an important role in treating multiple complex diseases. Yet, our ability to identify and validate effective combinations is limited by a combinatorial explosion, driven by both the large number of drug pairs as well as dosage combinations. Here we propose a network-based methodology to identify clinically efficacious drug combinations for specific diseases. By quantifying the network-based relationship between drug targets and disease proteins in the human protein-protein interactome, we show the existence of six distinct classes of drug-drug-disease combinations. Relying on approved drug combinations for hypertension and cancer, we find that only one of the six classes correlates with therapeutic effects: if the targets of the drugs both hit disease module, but target separate neighborhoods. This finding allows us to identify and validate antihypertensive combinations, offering a generic, powerful network methodology to identify efficacious combination therapies in drug development.
| S-EPMC6416394 | biostudies-literature
Project description:Several cancers are highly refractory to conventional chemotherapy. The survival of tumors in several cases is assisted by checkpoint immunomodulation to maintain the imbalance between immune surveillance and cancer cell proliferation. Check point antibody inhibitors, such as anti-PD-1/PD-L1, are a novel class of inhibitors that function as a tumor suppressing factor via modulation of immune cell-tumor cell interaction. These checkpoint blockers are rapidly becoming a highly promising cancer therapeutic approach that yields remarkable antitumor responses with limited side effects. In recent times, more than four check point antibody inhibitors have been commercialized for targeting PD-1, PDL-1, and CTLA-4. Despite the huge success and efficacy of the anti-PD therapy response, it is limited to specific types of cancers, which attributes to the insufficient and heterogeneous expression of PD-1 in the tumor microenvironment. Herein, we review the current landscape of the PD-1/PD-L1 mechanistic role in tumor immune evasion and therapeutic outcome for cancer treatment. We also review the current progress in clinical trials, combination of drug therapy with immunotherapy, safety, and future of check point inhibitors for multiple types of cancer.
| S-EPMC5572324 | biostudies-literature
Project description:Our aim was to analyse whether biomarkers extracted from baseline 18F-FDG PET before anti-PD1 treatment contribute to prognostic survival information for early risk stratification in metastatic melanoma. Fifty-six patients, without prior systemic treatment, BRAF wild type, explored using 18F-FDG PET were included retrospectively. Our primary endpoint was overall survival (OS). Total metabolic tumoral volume (MTV) and forty-one IBSI compliant parameters were extracted from PET. Parameters associated with outcome were evaluated by a cox regression model and when significant helped build a prognostic score. Median follow-up was 22.1 months and 21 patients died. Total MTV and long zone emphasis (LZE) correlated with shorter OS and served to define three risk categories for the prognostic score. For low, intermediate and high risk groups, survival rates were respectively 91.1% (IC 95 80-1), 56.1% (IC 95 37.1-85) and 19% (IC 95 0.06-60.2) and hazard ratios were respectively 0.11 (IC 95 0.025-0.46), P = 0.0028, 1.2 (IC 95 0.48-2.8), P = 0.74 and 5.9 (IC 95 2.5-14), P < 0.0001. To conclude, a prognostic score based on total MTV and LZE separated metastatic melanoma patients in 3 categories with dramatically different outcomes. Innovative therapies should be tested in the group with the lowest prognosis score for future clinical trials.
| S-EPMC8458464 | biostudies-literature
Project description:PD-L1 and PD-1 (PD) pathway blockade is a highly promising therapy and has elicited durable antitumor responses and long-term remissions in a subset of patients with a broad spectrum of cancers. How to improve, widen, and predict the clinical response to anti-PD therapy is a central theme in the field of cancer immunology and immunotherapy. Oncologic, immunologic, genetic, and biological studies focused on the human cancer microenvironment have yielded substantial insight into this issue. Here, we focus on tumor microenvironment and evaluate several potential therapeutic response markers including the PD-L1 and PD-1 expression pattern, genetic mutations within cancer cells and neoantigens, cancer epigenetics and effector T cell landscape, and microbiota. We further clarify the mechanisms of action of these markers and their roles in shaping, being shaped, and/or predicting therapeutic responses. We also discuss a variety of combinations with PD pathway blockade and their scientific rationales for cancer treatment.
| S-EPMC4859220 | biostudies-literature
Project description:Melanoma is the most malignant form of skin cancer, which seriously threatens human life and health. Anti-PD-1 immunotherapy has shown clinical benefits in improving patients' overall survival, but some melanoma patients failed to respond. Effective therapeutic biomarkers are vital to evaluate and optimize benefits from anti-PD-1 treatment. Although the establishment of immunotherapy biomarkers is well underway, studies that identify predictors by gene network-based approaches are lacking. Here, we retrieved the existing datasets (GSE91061, GSE78220 and GSE93157, 79 samples in total) on anti-PD-1 therapy to explore potential therapeutic biomarkers in melanoma using weighted correlation network analysis (WGCNA), function validation and clinical corroboration. As a result, 13 hub genes as critical nodes were traced from the key module associated with clinical features. After receiver operating characteristic (ROC) curve validation by an independent dataset (GSE78220), six hub genes with diagnostic significance were further recovered. Moreover, these six genes were revealed to be closely associated not only with the immune system regulation, immune infiltration, and validated immunotherapy biomarkers, but also with excellent prognostic value and significant expression level in melanoma. The random forest prediction model constructed using these six genes presented a great diagnostic ability for anti-PD-1 immunotherapy response. Taken together, IRF1, JAK2, CD8A, IRF8, STAT5B, and SELL may serve as predictive therapeutic biomarkers for melanoma and could facilitate future anti-PD-1 therapy.
| S-EPMC7230292 | biostudies-literature