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Anti-PD1 during T cell priming enhances long-term protection against metastatic tumors by epigenetically tuning T cell exhaustion

ABSTRACT: In cancer, CD8+ T cell responses are dominated by exhausted T cells, which can be reinvigorated using immune checkpoint blockade therapy and can control large tumors. However, it remains unclear which T cell fate best supports long-term immunity following initial tumor clearance or surgical resection when antigen is largely absent. To determine which T cell fate provides durable protection following surgical tumor removal and metastatic rechallenge, we modulated T cell priming using anti-PD-1, IFN-b or agonistic anti-CD40 and assessed effects on CD8+ T cell differentiation and overall survival. Strikingly, only treatment with anti-PD-1 but not IFN-b or anti-CD40 promoted improved long-term protection over surgical removal alone. Transcriptional and epigenetic profiling revealed that a circulatory, memory-like state sharing features of exhaustion characterizes the anti-tumor response during metastatic challenge in mice treated with anti-PD-1 and is associated with durable anti-tumor immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE346846 | GEO | 2026/09/10

REPOSITORIES: GEO

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Anti-PD1 during T cell priming enhances long-term protection against metastatic tumors by epigenetically tuning T cell exhaustion

Project description:In cancer, CD8+ T cell responses are dominated by exhausted T cells, which can be reinvigorated using immune checkpoint blockade therapy and can control large tumors. However, it remains unclear which T cell fate best supports long-term immunity following initial tumor clearance or surgical resection when antigen is largely absent. To determine which T cell fate provides durable protection following surgical tumor removal and metastatic rechallenge, we modulated T cell priming using anti-PD-1, IFN-b or agonistic anti-CD40 and assessed effects on CD8+ T cell differentiation and overall survival. Strikingly, only treatment with anti-PD-1 but not IFN-b or anti-CD40 promoted improved long-term protection over surgical removal alone. Transcriptional and epigenetic profiling revealed that a circulatory, memory-like state sharing features of exhaustion characterizes the anti-tumor response during metastatic challenge in mice treated with anti-PD-1 and is associated with durable anti-tumor immunity.

2026-09-10 | GSE335049 | GEO

Tumor and gut biopsies from refractory metastatic melanoma patients before and after treatment with fecal microbiota transplantation (FMT) and anti-PD-1 re-induction (Baruch et al, Science 2020)

Project description:We performed a phase I clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and re-induction of anti-PD-1 immunotherapy in patients with anti-PD-1-refractory metastatic melanoma. FMT donors were two metastatic melanoma patients who achieved a durable complete response. FMT recipient patients were metastatic melanoma patients who failed at least one anti-PD-1 line of treatment. Each recipient patient received FMT implants from only one of the two donors. FMT was conducted by both colonoscopy and oral ingestion of stool capsules, followed by anti-PD-1 re-treatment (Nivolumab, BMS). Recipient patients underwent pre- and post-treatment stool sampling, tissue biopsy of both gut and tumor, and total body imaging. Clinical responses were observed in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment.

2020-12-31 | GSE162436 | GEO

Whole Exome Predictors Immune Checkpoint Therapy Response in Renal Cell Carcinoma

Project description:<p>Immune checkpoint therapies, including monoclonal antibodies to programmed cell death-1 (PD-1) and cytotoxic % lymphocyte associated protein-4 (CTLA-4), yield durable clinical responses across many tumor types, including metastatic melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). However, predictors of response to these therapies in RCC are still unknown. Genomic characterization of large clinical cohorts of patients treated with anti-CTLA-4 and anti-PD-1 agents in melanoma and NSCLC have suggested that high mutational burden, high neoantigen burden, and high expression of certain genes in pre-treatment tumors may be associated with patient response to these therapies. In this study, we sought to investigate genomic predictors of response to anti-PD1 therapy in metastatic RCC in two independent clinical cohorts using whole exome and whole transcriptome sequencing.</p>

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Combined PD-L1/TGFb blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors

Project description:TGFb signaling is a major pathway associated with poor clinical outcome in patients with advanced metastatic cancers and non-response to immune checkpoint blockade, particularly in the immune-excluded tumor phenotype. While previous pre-clinical studies demonstrated that converting tumors from an excluded to an inflamed phenotype and curative anti-tumor immunity require attenuation of both PD-L1 and TGFb signaling, the underlying cellular mechanisms remain unclear. Recent studies suggest that stem cell-like CD8 T cells (TSCL) can differentiate into non-exhausted CD8 T effector cells that drive durable anti-tumor immunity. Here, we show that TGFb and PD-L1 restrain TSCL expansion as well as replacement of progenitor exhausted and dysfunctional CD8 T cells with non-exhausted IFNghi CD8 T effector cells in the tumor microenvironment (TME). Blockade of TGFb and PD-L1 generated IFNghi CD8 T effector cells with enhanced motility, enabling both their accumulation in the TME and increased interaction with other cell types. Ensuing IFNg signaling markedly transformed myeloid, stromal, and tumor niches to yield a broadly immune-supportive ecosystem. Blocking IFNg completely abolished the effect of anti-PD-L1/ TGFb combination therapy. Our data suggest that TGFb works in concert with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells with fresh CD8 T effector cells, thereby maintaining the CD8 T cell compartment in a dysfunctional state.

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2026-07-28 | GSE339275 | GEO

A Cryogel-Based Dendritic Cell Vaccine for Post-Surgical Breast Cancer Immunotherapy

Project description:Triple-negative breast cancer (TNBC) is an aggressive malignancy with high mortality and limited treatment options. While surgical resection removes the primary tumor, it often fails to prevent recurrence or metastasis, and despite the promise of immunotherapy, the response to immune checkpoint blockade remains poor. Here, we develop a cryogel-based dendritic cell (DC) vaccine that integrates gold nanodot-lipopolysaccharide (AuLPS)-loaded DCs, doxorubicin (Dox), and a PD-1 immune checkpoint blockade, effectively enhancing anti-tumor immunity in the post-surgical setting. The AuLPS nanoparticles (NPs) stabilize LPS assembly, optimizing Th1 adjuvant activity, thereby improving DC vaccine efficacy while minimizing adverse effects. The cryogel enables the sustained localized release of therapeutic agents at the surgical site, preserving DC viability, migration, and functionality within the tumor microenvironment. This strategy enhances DC activation and potentiates robust T-cell activation in both tumor-draining lymph nodes and tumor beds, leading to durable anti-tumor immunity. When administered at the post-surgical site in an orthotopic TNBC model, the aPD-1+Dox+AuLPS@DC cryogel vaccine significantly delays tumor recurrence, reduces distant metastases, and prolongs survival. These findings highlight cryogel-based DC vaccines as a promising post-surgical immunotherapy to overcome the limited response to immune checkpoint blockade and improve TNBC outcomes.

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Expression data from CD8 T cells from LCMV-Clone13 infected mice after two weeks of control or anti-PD-L1 treatment

Project description:Blocking PD-1 can reinvigorate exhausted CD8 T cells (TEX) and improve control of chronic infections and cancer. One potential advantage of this immunotherapy is durable protection if immune memory can be established. It is unclear, however, whether blocking PD-1 can reprogram TEX into effector (TEFF) or durable memory T cells (TMEM). Here, we found reinvigoration of TEX by PD-L1 blockade caused re-acquisition of some features of TEFF, but minimal memory development. We used microarray analysis to profile exhausted cells from anti-PD-L1 mice after two weeks of treatment to study if PD-L1 blockade caused re-acquistion of some feature of effector or memory cells.

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2020-05-10 | GSE150176 | GEO

Transcription profiling of human cutaneous tumors to identify gene expression patterns involved in the malignant transformation and progression of metastatic melanoma

Project description:Metastatic melanoma is a deadly disease while non-metastatic melanoma and other cutaneous tumor types are usually cured with surgical removal of the primary tumors. This study evaluated gene expresion to determine if gene expression differences existed which would allow one to identify the metastatic tumors based on the expression of specific genes. Experiment Overall Design: Tumor samples were collected from patients with various cutaneous tumors, flash frozen, and then processed for gene exprression analysis using microarrays. The pool of tissues includes enough metastatic samples and non-metastatic samples to identify a gene expression signature associated with the outgrowth of the metastatic tumor.

2008-06-18 | E-GEOD-7553 | biostudies-arrayexpress

Liu2019 - Logistic Regression models to predict intrinsic resistance to anti-PD1 ICB in Ipilimumab treated and Ipilimumab naive patients with metastatic melanoma.

Project description:In this comprehensive study, the authors have developed concise models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 Immune Checkpoint Blockade (ICB) treatment in individual tumors. It's important to note that their validation was performed in smaller, independent cohorts, constrained by data availability. The authors have developed two Logistic Regression based models for Ipilimumab treated and Ipilimumab naive patients with metastatic melanoma. The main predictive features for the Ipilimumab treated patients are MHC-II HLA, LDH at treatment initiation and the presence of lymph node metastases (LN met), chosen using forward selection methodology. The main predictive features for the Ipilimumab naive patients are tumor heterogeneity, tumor ploidy and tumor purity, chosen using forward selection methodology. Please note that in these models, the output ‘1’ means progressive disease (PD) and ‘0’ means non-PD. The original GitHub repository can be accessed at https://github.com/vanallenlab/schadendorf-pd1

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