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PD-1 checkpoint blockade disrupts CD4 T cell regulated adaptive B cell tolerance to foreign antigengs

ABSTRACT: We utilized single cell-indexed custom RNA-sequencing to interogate the transcriptomes of IgG1 specific germinal center B cells and Plasma cells at steady state and six days after actue antibody mediated PD1 blockade

ORGANISM(S): Mus musculus

PROVIDER: GSE205116 | GEO | 2022/06/03

REPOSITORIES: GEO

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Isotype-specific plasma cells express divergent transcriptional programs

Project description:We utilized single cell-indexed custom RNA-sequencing to interogate the transcriptomes of isotype specific plasma cells at homeostasis and following immunization with a model antigen

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Evolution of antigen-specific follicular helper T cell transcriptional progams across effector function and through to memory

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PD-L1 checkpoint blockade promotes regulatory T-cell suppressive capacity underlying immunotherapy resistance

Project description:Transcriptome analyses of isotype-treated and aPD-L1-treated CD4+ T-cells, PD1- Treg cells and PD1+ Treg cells from a mouse model for mesothelioma.

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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.

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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.

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PD-1 checkpoint blockade disrupts CD4 T cell regulated adaptive B cell tolerance to foreign antigengs

Project description:PD-1 checkpoint blockade disrupts CD4 T cell regulated adaptive B cell tolerance to foreign antigengs

| PRJNA843940 | ENA

Qualitative changes in activated T cells induced by checkpoint blockade in vivo

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2021-07-30 | GSE165818 | GEO

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