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Immunosuppressive CD29+ Treg accumulation in the liver in mice upon checkpoint inhibitor therapy

ABSTRACT: We report that anti-PD1 treatment expands regulatory T cells (Tregs) in the liver of tumor-bearing mice and this contributes to the resistance mechanism of metastatic liver cancer to immunotherapy. Using FoxP3-GFP strain, Tregs after anti-PD1 treatment were sorted and Tregs from the liver and spleen were sequenced. CD29 positive cluster expanded in PD1-treated mouse liver. CD29-positive Tregs had also a suppression function in vitro validation study. And we identified CD29-positive Tregs in the public database of human liver cancer. We propose that CD29+ Tregs constitute a unique subpopulation of hepatic Tregs that are primed to respond to ICI agents and mediate resistance.

ORGANISM(S): Mus musculus

PROVIDER: GSE221186 | GEO | 2023/12/16

REPOSITORIES: GEO

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Innate immune checkpoint inhibitor resistance is associated with melanoma sub-types exhibiting invasive and de-differentiated gene expression signatures

Project description:Melanoma is a highly aggressive skin cancer, which, although highly immunogenic, frequently escapes the body’s immune defences. Immune checkpoint inhibitors (ICI), such as anti-PD1, anti-PDL1, and anti-CTLA4 antibodies lead to reactivation of immune pathways, promoting rejection of melanoma. However, the benefits of ICI therapy remain limited to a relatively small proportion of patients who do not exhibit ICI resistance. Moreover, the precise mechanisms underlying innate and acquired ICI resistance remain unclear. Here, we have investigated differences in melanoma tissues in responder and non-responder patients to anti-PD1 therapy in terms of tumour and immune cell gene-associated signatures.

2022-09-15 | GSE213145 | GEO

Spatial immunophenotypes predict response to anti-PD1 treatment and capture distinct paths of T-cell evasion in triple negative breast cancer

Project description:Only a subgroup of triple-negative breast cancer (TNBC) responds to immune checkpoint inhibitors (ICI). To better understand lack of response to ICI, we analyzed 681 TNBCs for spatial immune cell contextures in relation to clinical outcomes as well as pathways of T-cell evasion. Excluded, ignored and inflamed phenotypes were captured by a gene classifier that predicts prognosis of various cancers as well as anti-PD1 response of metastatic TNBC patients in a phase II trial. The excluded phenotype, which was associated with resistance to anti-PD1, demonstrated deposits of collagen-10, enhanced glycolysis, and activation of TGFb/VEGF pathways; the ignored phenotype, also associated with resistance to anti-PD1, showed either high density of CD163+ myeloid cells or activation of WNT/PPARg pathways; whereas the inflamed phenotype, which was associated with response to anti-PD1, revealed necrosis, high density of CLEC9A+ dendritic cells, high TCR clonality independent of neo-antigens, and enhanced expression of T-cell co-inhibitory receptors.

2021-06-12 | GSE177043 | GEO

Impact of Diet and aPD1 on CD8 metabolism

Project description:Only a small fraction of patients with HCC benefit from immune checkpoint inhibitor (ICI) therapy. Recently published studies suggest that HCC in patients with NASH does not respond the ICI therapy. Indeed, we demonstrate that anti-PD1 therapy is not working in several murine NASH models. CD8+ T cells were identified as the effector of anti-PD1 therapy. We observed a proinflammatory phenotype if hepatic CD8+ T cells that does not explain the inefficacy of anti-PD1 therapy in NASH. However, our study revealed an impairment of intratumoral CD8+ T cells movement abilities in NASH. Additionally, a broad reduction of metabolic fitness was observed in hepatic CD8+ T cells NASH. This was restored by metformin treatment. The combination treatment of anti-PD1 and metformin reduced intrahepatic tumor burden in NASH, a finding with important implications for NASH patients. This GEO submission contains raw files for the CD8 nsolver microarray analyses.

2022-03-31 | GSE184231 | GEO

Checkpoint blockade induced CD8+ T cell differentiation in responders in head and neck cancers

Project description:Background: Outcomes for locally advanced or recurrent/ metastatic head and neck squamous cell carcinomas (HNSCCs) remain unfavorable despite recent advances with immune checkpoint blockade (ICB). Preclinical studies using model antigens identified a critical role of CD8+TCF7+PD1+ T cells in anti-PD1 response. Studies on the heterogeneity and clonal dynamics of global tumor infiltrating T lymphocytes (TILs) in the HNSCC anti-PD1 and anti-CTLA4 response have not been explored. Results: In this study, we generated isogenic HNSCC anti-PD1 sensitive/resistant models that bore distinct cancer cell intrinsic transcriptomic programs. Tumor microenvironment characterization using mass cytometry and targeted depletion revealed the contribution of Tregs and M2-like macrophages in anti-PD1 resistance. Paired single-cell RNA and TCR sequencing on tumor infiltrating immune cells from ICB responsive and resistant HNSCC models identified a spectrum of CD8+ TIL subsets including TCF7+PD1- (naïve/memory-like), TCF7+PD1+ (progenitor exhausted), and TCF7-PD1+ (terminally exhausted). Mapping TCR shared fractions between these subsets identified that successful anti-PD1 or anti-CTLA4 therapy induced higher post-treatment T cell lineage transitions. A TIL differentiation gene signature was associated with better responses in multiple ICB clinical trials. Conclusions: Together, analyses integrating scRNAseq and TCRseq demonstrate distinct differentiation dynamics of CD8+ TILs in novel ICB responsive and resistant HNSCC models, highlighting critical aspects of CD8+ TIL differentiation in response to ICB.

2021-12-01 | GSE153383 | GEO

Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis

Project description:we performed bulk RNA sequencing assessing transcriptomics and pathways affected in our mouse model. In ICI-myocarditis mice (ctla4+/-pd1-/-), bulk RNA sequencing showed very distinct affected pathways in ICI-myocarditis mice compared to unaffected control mice (ctla4+/+ pd1-/-).

2023-02-13 | GSE225099 | GEO

ena-DATASET-BRFAA-25-09-2020-10:04:32:455-153 - samples

Project description:Tregs were sorted as CD4+CD25+CD127- cells from peripheral blood of patients with advanced metastatic melanoma, stage III(B-D)-IV, who were receiving treatment with anti-PD1 (n =26); and patients with kidney, non-small cell lung, liver and bladder cancer who were receiving treatment with anti-PD1. RNA was extracted and polyA libraries were prepared using the Illumina Truseq sample preparation kit v.2. Single-end sequencing was performed on NextSeq500.

| EGAD00001006415 | EGA

Inactivation of interferon signaling promotes the establishment of an immunosuppressive microenvironment in colorectal cancers

Project description:Tumors arise and grow despite anti-cancer immune responses. These responses can be stimulated by immunotherapies such as immune checkpoint inhibitors (e.g. anti-PD1 antibodies) and chimeric antigen receptors (CAR). Efficacy of these agents in solid tumors including colorectal cancers (CRC) is limited by immunosuppressive tumor microenvironment (TME) that prevents killing of malignant cells by cytotoxic T lymphocytes (CTL). Understanding the nature of TME-generated immunosuppression is of paramount importance. Here we report that TME elicited immunosuppression via eliminating activated CTL; this elimination required TME stress-induced downregulation of the IFNAR1 chain of type I interferon (IFN) receptor and attenuation of its signaling. Downregulation of IFNAR1 was observed in human colorectal cancers (CRC) and in mouse CRC models where it was required for efficient tumor development and progression. Stabilization of IFNAR1 on CTL improved their survival and increased anti- tumor activities of CAR T cells and PD1 inhibitors thereby providing a rationale for targeting IFNAR1 degradation for immunotherapies optimization. Two genotypes of mice were examined either 9 or 21 days post injection of MC38 colon cancer cells or MC38mRFP cells, respectively. 2-3 replicate mice were analyzed on separate arrays for each condition. 6 conditions in total were analyzed.

2016-01-15 | E-GEOD-76889 | biostudies-arrayexpress

Molecular patterns of resistance to immune checkpoint blockade in melanoma [scRNA-Seq]

Project description:Immune checkpoint blockade (ICB) has improved outcome for patients with metastatic melanoma but not all benefit from treatment. Several immune- and tumor intrinsic features are associated with clinical response at baseline. However, we need to further understand the molecular changes occurring during development of ICB resistance. Here, we collected biopsies from a cohort of 44 melanoma patients after progression to anti-CTLA4 or anti-PD1 monotherapy. Genetic alterations of antigen presentation and interferon gamma signaling pathways were observed in approximately 25% of ICB resistant cases. Anti-CTLA4 resistant lesions had a sustained immune response, including immune-regulatory features, as suggested by multiplex spatial and TCR clonality analyses. One anti-PD1 resistant lesion harbored a distinct immune cell niche, however, anti-PD1 resistant tumors were generally immune poor with non-expanded TCR clones. Such immune poor microenvironments were associated with melanoma cells having a de-differentiated phenotype lacking expression of MHC-I molecules. In addition, anti-PD1 resistant tumors had reduced fractions of PD1+ CD8+ T cells as compared to ICB naïve metastases. Collectively, these data show the complexity of ICB resistance and highlight differences between anti-CTLA4 and anti-PD1 resistance that may underlie differential clinical outcomes of therapy sequence and combination.

2024-02-06 | GSE244983 | GEO

Molecular patterns of resistance to immune checkpoint blockade in melanoma [bulk RNA-Seq]

2024-02-06 | GSE244982 | GEO

Bone morphogenetic protein 7 promotes resistance to immunotherapy

Project description:We previously generated a syngeneic preclinical model of NSCLC (p53R172HΔg/+KrasLA1/+) with acquired resistance to anti-PD1. In the current study, we investigated methylation differences in specific genomic regions comparing anti-PD1-resistant tumors (344SQR) with their parental-tumor counterparts (344SQP).

2020-08-17 | GSE154993 | GEO

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