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Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8 T cells [dataset 4]

ABSTRACT: Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. We performed RNA+TCR single-cell analysis across time in 36 stage IV melanoma patients treated with anti-PD-1, anti-CTLA-4, or combination therapy. We developed the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induced waves of clonal T cell responses that peaked at distinct timepoints. Combination therapy resulted in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8 T cells and exhausted CD8 T cell (TEX) clones. Focused analyses of TEX identified that anti-CTLA-4 induced robust expansion and proliferation of progenitor TEX, which synergized with anti-PD-1 to reinvigorate TEX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273718 | GEO | 2024/08/01

REPOSITORIES: GEO

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Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8 T cells [dataset 1]

Project description:Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. We performed RNA+TCR single-cell analysis across time in 36 stage IV melanoma patients treated with anti-PD-1, anti-CTLA-4, or combination therapy. We developed the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induced waves of clonal T cell responses that peaked at distinct timepoints. Combination therapy resulted in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8 T cells and exhausted CD8 T cell (TEX) clones. Focused analyses of TEX identified that anti-CTLA-4 induced robust expansion and proliferation of progenitor TEX, which synergized with anti-PD-1 to reinvigorate TEX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.

2024-07-30 | GSE272993 | GEO

Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8 T cells [dataset 3]

2024-07-30 | GSE272735 | GEO

Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8 T cells [dataset 2]

2024-07-30 | GSE272734 | GEO

Gene Expression Profiling of human monocytes: Combination Therapy with AntiâCTLA-4 and AntiâPD-1 Leads to Distinct Immunologic Changes In Vivo

Project description:Transcriptome analysis of human peripheral blood monocytes Combination therapy concurrently targeting PD-1 and CTLA-4 immune checkpoints leads to remarkable antitumor effects. Although both PD-1 and CTLA-4 dampen the T cell activation, the in vivo effects of these drugs in humans remain to be clearly defined. To better understand biologic effects of therapy, we analyzed blood/tumor tissue from patients undergoing single or combination immune checkpoint blockade. We show that blockade of CTLA-4, PD-1, or combination of the two leads to distinct genomic (changes in gene-expression profile) and functional signatures in vivo in purified human T cells and monocytes. RNA extracted from freshly isolated monocytes from peripheral blood of patients treated with either antiâPD-1 (n = 6), antiâCTLA-4 (n = 5), Combo therapy with antiâPD-1 and antiâCTLA-4 concurrently (Combo, n = 6), and Seq antiâPD-1 in patients with prior antiâCTLA-4 (Seq, n = 3) was analyzed using the Affymetrix GeneChip Human Transcriptome 2.0 exon array. No techinical replicates were performed.

2016-02-16 | E-GEOD-77924 | biostudies-arrayexpress

Gene Expression Profiling of human T cells: Combination Therapy with Antiâ??CTLA-4 and Antiâ??PD-1 Leads to Distinct Immunologic Changes In Vivo

Project description:Transcriptome analysis of human peripheral blood T cells Combination therapy concurrently targeting PD-1 and CTLA-4 immune checkpoints leads to remarkable antitumor effects. Although both PD-1 and CTLA-4 dampen the T cell activation, the in vivo effects of these drugs in humans remain to be clearly defined. To better understand biologic effects of therapy, we analyzed blood/tumor tissue from patients undergoing single or combination immune checkpoint blockade. We show that blockade of CTLA-4, PD-1, or combination of the two leads to distinct genomic (changes in gene-expression profile) andfunctional signatures in vivo in purified human T cells. RNA extracted from freshly isolated T cells from peripheral blood of patients treated with either antiâ??PD-1 (n = 6), antiâ??CTLA-4 (n = 5), Combo therapy with antiâ??PD-1 and antiâ??CTLA-4 concurrently (Combo, n = 6), and Seq antiâ??PD-1 in patients with prior antiâ??CTLA-4 (Seq, n = 3) was analyzed using the Affymetrix GeneChip Human Transcriptome 2.0 exon array. No techinical replicates were performed.

2016-02-10 | E-GEOD-77714 | biostudies-arrayexpress

Decitabine-induced T cell remodeling facilitates a high antitumor response to PD-1 blockade therapy by promoting the expansion and effector function of CD8+ progenitor exhausted T cells

Project description:CD8+ exhausted T (Tex) cells are heterogeneous with distinct transcriptional and epigenetic landscapes. PD-1 inhibitors reinvigorate progenitor Tex cells, which subsequently differentiate into irresponsive terminal Tex cells and impair the longlasting antitumor response of PD-1 blockade therapy. How to maintain durable proliferative capacity of progenitor Tex cells is important but remains largely unknown. Here, we showed that low-dose DNA demethylating agent decitabine-pretreated CD8+ progenitor Tex cells had enhanced cytolytic activity against tumors after anti-PD-1 treatment in vitro and could not reactivate the terminal Tex cells. Decitabine-plus-anti-PD-1 treatment promoted the activation and expansion of endogenous tumor-infiltrated CD8+ progenitor Tex cells and efficiently suppressed tumor growth in multiple mice tumor models. The single-cell RNA-sequencing, TCR-sequencing and ATAC-sequencing demonstrated that decitabine-plus-anti-PD-1 combination altered the transcriptional and epigenetic status of CD8+ Tex cells and markedly elevated the clonally expansion and effector function of progenitor Tex cells as compared with anti-PD-1 monotherapy, presenting increased expression of genes associated with T cell activation, proliferation, cytolytic activity, memory and mitochondrial metabolism. Strikingly, decitabine-plus-anti-PD-1 combination sustained the expression and activity of AP-1 transcription factor JunD, which was reduced following PD-1 blockade therapy. Suppressing JNK/AP-1 signaling in CD8+ T cells blunted decitabine-plus-anti-PD-1-induced activation of CD8+ T cells. Together, our findings show that the epigenetic therapy remodels CD8+ progenitor Tex subset, improves responsiveness to anti-PD-1 therapy and suppresses CD8+ T cell terminal differentiation.

2022-07-28 | GSE209965 | GEO

Patient-derived xenograft platform for metastatic melanoma: RNA sequencing of 95 melanoma PDX samples

Project description:Although high clinical response rates are seen for immune checkpoint blockade (ICB) of metastatic melanoma, both intrinsic and acquired ICB resistance remain formidable challenges. Combination ICB shows improved clinical benefit, but is associated with severe adverse events and exceedingly high cost. Therefore, there is a dire need to stratify individual patients for their likelihood of responding to either anti-PD-1 or anti-CTLA-4 monotherapy, or the combination. Since it is conceivable that ICB responses are influenced by both tumor cell-intrinsic and stromal factors, we hypothesized that a predictive classifier ought to mirror both of these distinct features. We used a panel of melanoma patient-derived xenografts (PDX), in which human stromal cells upon transplantation are naturally replaced by their murine counterparts, to computationally subtract PDX RNA expression signals from those in patients’ melanomas. We thus derived both “Stromal immune” (SIM) and tumor cell-specific “Tumor-autonomous inflammation” (TAF) signatures. Here we report that the SIM signature predicts response to anti-CTLA-4 but not anti-PD-1 treatment, whereas the tumor TAF signature predicts response to anti-PD-1 but not anti-CTLA-4. Moreover, when used in conjunction, the signatures accurately predict response in two independent patient cohorts treated with the anti-CTLA-4 + anti-PD-1 combination. These signatures may be clinically exploited for personalized treatment advice based on the predicted benefit from either anti-CTLA-4 or anti-PD-1 monotherapy or their combination.

2020-04-27 | GSE129127 | GEO

Gene Expression Profiling of human T cells: Combination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo

2016-02-10 | GSE77714 | GEO

Gene Expression Profiling of human monocytes: Combination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo

2016-02-16 | GSE77924 | GEO

Combined blockade of B7-H3 and CD47 immune checkpoints is a new therapeutic strategy for β-catenin driven melanomas [transfection]

Project description:In melanoma, immune cell infiltration into the tumor is associated with better patient outcomes and response to immunotherapy. T cell non-inflamed tumors (‘cold tumors’) are associated with tumor cell intrinsic Wnt/β-catenin activation, and are resistant to anti-PD-1 alone or in combination with anti-CTLA-4 therapy. Reversal of the ‘cold tumor’ phenotype and identifying new effective immunotherapies are challenges in melanoma. In a well-established preclinical melanoma model driven by β-catenin, we found that immune checkpoint molecule B7-H3 confers a suppressive tumor microenvironment by modulating antiviral signals and matricellular proteins. Its inhibition primes the microenvironment, and together with blockade of the macrophage checkpoint CD47, but not with anti-PD-1, results in synergistic anti-tumor responses. This study brings B7-H3 to the forefront as inducing a suppressive microenvironment when overexpressed, and co-targeting with CD47 as a novel combination of immune checkpoint inhibitors in melanoma that calls for testing in clinical trials.

2023-10-30 | GSE155394 | GEO

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