Pan-tumor genomic biomarkers for personalization of PD-1 checkpoint blockade based immunotherapy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA449579 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Pan-tumor genomic biomarkers for personalization of PD-1 checkpoint blockade based immunotherapy
| PRJNA449580 | ENA
Project description:An improved understanding of the anti-tumor CD8+ T cell response after checkpoint blockade would enable more informed and effective therapeutic strategies. Here we examined the dynamics of the effector response of CD8+ tumor-infiltrating lymphocytes (TILs) after checkpoint blockade therapy. Bulk and single-cell RNA profiles of CD8+ TILs after combined Tim-3+PD-1 blockade in preclinical models revealed significant changes in the transcriptional profile of PD-1? TILs. These cells could be divided into subsets bearing characterstics of naive-, effector-, and memory-precursor-like cells. Effector- and memory-precursor-like TILs contained tumor-antigen-specific cells, exhibited proliferative and effector capacity, and expanded in response to different checkpoint blockade therapies across different tumor models. The memory-precursor-like subset shared features with CD8+ T cells associated with response to checkpoint blockade in patients and was compromised in the absence of Tcf7. Expression of Tcf7 was requisite for the efficacy of diverse immunotherapies, highlighting the importance of this transcriptional regulator in the development of effective CD8+ T cell responses upon immunotherapy.
2019-01-16 | GSE122969 | GEO
Project description:Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell-inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti-PD-1 monotherapy and combination immunotherapy regimens.
| S-EPMC6718162 | biostudies-literature
Project description:Cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and Programmed death-1 (PD-1) are immunoregulatory receptors expressed on T cells that play important roles in suppressing immune responses to cancer. Although monoclonal antibodies that target CTLA-4 or PD-1 stimulate therapeutic anti-tumour T cell responses, the tumour antigens recognized by checkpoint blockade immunotherapy remain undefined. Herein, we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T cell rejection antigens following αPD-1 and/or αCTLA-4 treatment of mice bearing progressively growing sarcomas. We validate this conclusion by showing that (a) the predicted mutant epitopes associate with MHC class I molecules of the tumour; (b) T cells specific for these mutant epitopes infiltrate tumours; and (c) therapeutic vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Whereas, T cells with the same antigen specificity are present in progressively growing tumours in control mice, tumour-specific T cells in αPD-1- and/or αCTLA-4-treated mice express some overlapping but mostly treatment-specific transcriptional profiles that render them capable of tumour rejection. Thus, tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy but also can be used to identify tumour antigen-specific T cells that function as biomarkers of successful anti-tumour responses.
2014-11-07 | GSE62771 | GEO
Project description:Immunotherapy study of phagocytosis checkpoint blockade in combination with radiotherapy
| PRJNA812010 | ENA
Project description:Checkpoint blockade immunotherapy induces dynamic changes in PD-1-CD8+ tumor-infiltrating T cells
| PRJNA507017 | ENA
Project description:Tissue specific innate lymphoid cells promote checkpoint blockade PD-1 immunotherapy in pancreatic cancer
| PRJNA531149 | ENA
Project description:Trained immunity-promoting nanobiologics suppress tumor growth and potentiate checkpoint blockade immunotherapy
| PRJNA523329 | ENA
Project description:Immune checkpoint blockade is able to achieve durable responses in a subset of patients, however we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4 and anti-PD-1 induced tumor rejection. To address these issues we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint blockade induced immune responses are driven by distinct cellular mechanisms.
2017-08-10 | GSE100808 | GEO
Project description:Checkpoint blockade immunotherapy has become a first-line treatment option for cancer patients, with success in increasingly diverse cancer types. Still, many patients do not experience durable responses and the reasons for clinical success versus failure remain largely undefined. Investigation of immune responses within the tumor microenvironment can be highly informative but access to tumor tissue is not always available, highlighting the need to identify biomarkers in the blood that correlate with clinical success. Here, we used single-cell RNA sequencing coupled with T cell receptor sequencing to define CD8+ T cell responses in peripheral blood of two patients with melanoma before and after immunotherapy with either anti-PD-1 (nivolumab) alone or the combination of anti-PD-1 and CTLA-4 (ipilimumab). Both treatment regimens increased transcripts associated with cytolytic effector function and decreased transcripts associated with naive T cells. These responses were further evaluated at the protein level and extended to a total of 53 patients with various cancer types. Unexpectedly, the induction of CD8+ T cell responses associated with cytolytic function was variable and did not predict therapeutic success in this larger patient cohort. Rather, a decrease in the frequency of T cells with a naive-like phenotype was consistently observed after immunotherapy and correlated with prolonged patient survival. In contrast, a more detailed clonotypic analysis of emerging and expanding CD8+ T cells in the blood revealed that a majority of individual T cell clones responding to immunotherapy acquired a transcriptional profile consistent with cytolytic effector function. These results suggest that responses to checkpoint blockade immunotherapy are evident and traceable in patients’ blood, with outcomes predicted by the simultaneous loss of naive-like CD8+ T cells and the expansion of mostly rare and diverse cytotoxic CD8+ T cell clones.
2022-08-23 | GSE211504 | GEO