Similar Datasets
Project description:The on/off dynamics of IFNβ signalling underlie the therapeutic response to immune checkpoint therapy in cancer, which can be exploited to sway the clinical trajectory in favour of response
2020-12-07 | GSE153941 | GEO
Project description:The on/off dynamics of IFNβ signalling underlie the therapeutic response to immune checkpoint therapy in cancer, which can be identified in Ly6C+ monocytes
2022-06-12 | GSE153942 | GEO
Project description:Dynamic IFNβ signalling underlies treatment response to immune checkpoint therapy in cancer
| PRJNA644586 | ENA
Project description:Dynamic IFNβ signalling underlies treatment response to immune checkpoint therapy in cancer [bulk RNA-seq]
| PRJNA644589 | ENA
Project description:The biological determinants of the response to immune checkpoint blockade (ICB) in cancer remain incompletely understood. Little is known about dynamic biological events that underpin therapeutic efficacy due to the inability to frequently sample tumours in patients. Here, we map the transcriptional profiles of 144 responding and non-responding tumours within two mouse models at four time points during ICB. We find that responding tumours display on/fast-off kinetics of type-I-interferon (IFN) signaling. Phenocopying of this kinetics using time-dependent sequential dosing of recombinant IFNs and neutralizing antibodies markedly improves ICB efficacy, but only when IFNβ is targeted, not IFNα. We identify Ly6C+/CD11b+ inflammatory monocytes as the primary source of IFNβ and find that active type-I-IFN signaling in tumour-infiltrating inflammatory monocytes is associated with T cell expansion in patients treated with ICB. Together, our results suggest that on/fast-off modulation of IFNβ signaling is critical to the therapeutic response to ICB, which can be exploited to drive clinical outcomes towards response.
| S-EPMC9390963 | biostudies-literature
Project description:Bladder cancer remains the most immunogenic and expensive malignant tumor in the United States today. As the 4th leading cause of death from cancer in United States, Immunotherapy blocking immune checkpoints have been recently been applied to many aggressive cancers and changed interventions of urological cancers including advanced bladder cancer. The applied inhibition of PD-1-PD-L1 interactions can restore antitumor T-cell activity and enhance the cellular immune attack on antigens. The overall goals of this short review article are to introduce current cancer immunotherapy and immune checkpoint inhibitors, and to provide new insight into the underlying mechanisms that block immune checkpoints in tumor microenvironment. Furthermore, this review will address the preclinical and clinical trials to determine whether bladder cancer patients could benefit from this new cancer therapy in near future.
| S-EPMC4910761 | biostudies-literature
Project description:Importance:Gut dysbiosis impairs response to immune checkpoint inhibitors (ICIs) and can be caused by broad-spectrum antibiotic (ATB) therapy. Objective:To evaluate whether there is an association between ATB therapy administered concurrently (cATB) or prior (pATB) to ICI therapy and overall survival (OS) and treatment response to ICI therapy in patients with cancer treated with ICIs in routine clinical practice. Design, Setting, and Participants:This prospective, multicenter, cohort study conducted at 2 tertiary academic referral centers recruited 196 patients with cancer who received ICI therapy between January 1, 2015, and April 1, 2018, in routine clinical practice rather than clinical trials. Main Outcomes and Measures:Overall survival calculated from the time of ICI therapy commencement and radiologic response to ICI treatment defined using the Response Evaluation Criteria in Solid Tumors (version 1.1), with disease refractory to ICI therapy defined as progressive disease 6 to 8 weeks after the first ICI dose without evidence of pseudoprogression. Results:Among 196 patients (137 men and 59 women; median [range] age, 68 [27-93] years) with non-small cell lung cancer (n?=?119), melanoma (n?=?38), and other tumor types (n?=?39), pATB therapy (HR, 7.4; 95% CI, 4.3-12.8; P?<?.001), but not cATB therapy (HR, 0.9; 95% CI, 0.5-1.4; P?=?.76), was associated with worse OS (2 vs 26 months for pATB therapy vs no pATB therapy, respectively) (hazard ratio [HR], 7.4; 95% CI, 4.2-12.9) and a higher likelihood of primary disease refractory to ICI therapy (21 of 26 [81%] vs 66 of 151 [44%], P?<?.001). Overall survival in patients with non-small cell lung cancer (2.5 vs 26 months, P?<?.001), melanoma (3.9 vs 14 months, P?<?.001), and other tumor types (1.1 vs 11, P?<?.001) was consistently worse in those who received pATBs vs those who did not. Multivariate analyses confirmed that pATB therapy (HR, 3.4; 95% CI, 1.9-6.1; P?<?.001) and response to ICI therapy (HR, 8.2; 95% CI, 4.0-16.9; P?<?.001) were associated with OS independent of tumor site, disease burden, and performance status. Conclusions and Relevance:Despite being limited by sample size, geographic origin, and the lack of correlative analyses on patients' gut microbiota, this study suggests that pATB therapy but not cATB therapy is associated with a worse treatment response and OS in unselected patients treated with ICIs in routine clinical practice. Mechanistic studies are urgently required to investigate ATB-mediated alterations of gut microbiota as a determinant of poorer outcome following ICI treatment.
| S-EPMC6743060 | biostudies-literature
Project description:Despite lengthening survival, death rates from metastatic colorectal cancer (CRC) remain unacceptably high, with a bright spot being the demonstration of durable responses in patients with CRC who have mismatch repair-deficient (dMMR) and/or microsatellite instability-high (MSI-H) tumors and are treated with immune checkpoint inhibitor therapy. Nivolumab and pembrolizumab, as well as nivolumab in combination with low-dose ipilimumab-all checkpoint inhibitors-are currently approved by the U.S. Food and Drug Administration (FDA) for patients with MSI-H/dMMR metastatic CRC that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Nonetheless, there are a number of questions and considerations in the use of these checkpoint inhibitor therapies. Using a question-and-answer format, this review summarizes the scientific rationale for immune checkpoint inhibitor therapy in CRC, including the effects of tumor factors such as genetic aberrations and mutational load on the immune response, particularly in patients with MSI-H/dMMR disease. We discuss response patterns, response criteria, and immune-related adverse events using findings from published efficacy and safety data of immune checkpoint inhibitor therapy in metastatic CRC. We also discuss issues surrounding treatment sequencing, incorporating approved checkpoint inhibitors into the current treatment paradigm, and the multiple investigational strategies that may optimize immunotherapy for advanced CRC in the future, including novel combination therapies. IMPLICATIONS FOR PRACTICE: Colorectal cancer (CRC) is the third most common cancer in the U.S. Despite advances in chemotherapy, survival remains poor for patients with metastatic CRC. Certain immunotherapy agents have demonstrated long-lasting responses in previously treated patients with immune-responsive microsatellite instability-high/mismatch repair-deficient metastatic CRC, leading to U.S. Food and Drug Administration approval of the immune checkpoint inhibitors nivolumab (with or without low-dose ipilimumab) and pembrolizumab in this population. Combination therapy (e.g., nivolumab with low-dose ipilimumab) has demonstrated numerically higher response rates and improved long-term clinical benefit relative to anti-programmed death-1 monotherapy. Ongoing trials are evaluating immunotherapy in the broader CRC population and novel combinations to optimize immunotherapy for advanced CRC.
| S-EPMC6964145 | biostudies-literature
Project description:Immune checkpoints include stimulatory and inhibitory checkpoint molecules. In recent years, inhibitory checkpoints, including cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death ligand 1 (PD-L1), have been identified to suppress anti-tumor immune responses in solid tumors. Novel drugs targeting immune checkpoints have succeeded in cancer treatment. Specific PD-1 blockades were approved for treatment of melanoma in 2014 and for treatment of non-small-cell lung cancer in 2015 in the United States, European Union, and Japan. Preclinical and clinical studies show immune checkpoint therapy provides survival benefit for greater numbers of patients with liver cancer, including hepatocellular carcinoma and cholangiocarcinoma, two main primary liver cancers. The combination of anti-PD-1/PD-L1 with anti-CTLA-4 antibodies is being evaluated in phase 1, 2 or 3 trials, and the results suggest that an anti-PD-1 antibody combined with locoregional therapy or other molecular targeted agents is an effective treatment strategy for HCC. In addition, studies on activating co-stimulatory receptors to enhance anti-tumor immune responses have increased our understanding regarding this immunotherapy in liver cancer. Epigenetic modulations of checkpoints for improving the tumor microenvironment also expand our knowledge of potential therapeutic targets in improving the tumor microenvironment and restoring immune recognition and immunogenicity. In this review, we summarize current knowledge and recent developments in immune checkpoint-based therapies for the treatment of hepatocellular carcinoma and cholangiocarcinoma and attempt to clarify the mechanisms underlying its effects.
| S-EPMC5975687 | biostudies-literature
Project description:In recent years immune checkpoint inhibitors have garnered attention as being one of the most promising types of immunotherapy on the horizon. There has been particular focus on the immune checkpoint molecules, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) which have been shown to have potent immunomodulatory effects through their function as negative regulators of T cell activation. CTLA-4, through engagement with its ligands B7-1 (CD80) and B7-2 (CD86), plays a pivotal role in attenuating the activation of naïve and memory T cells. In contrast, PD-1 is primarily involved in modulating T cell activity in peripheral tissues via its interaction with PD-L1 and PD-L2. The discovery of these negative regulators of the immune response was crucial in the development of checkpoint inhibitors. This shifted the focus from developing therapies that targeted activation of the host immune system against cancer to checkpoint inhibitors, which aimed to mediate tumor cell destruction through the removal of coinhibitory signals blocking anti-tumor T cell responses.
| S-EPMC6163118 | biostudies-literature