Corticosteroid premedication and the antitumor effect of immune checkpoint blockade in murine hepatocellular carcinoma models
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE281699 | GEO | 2025/01/31
REPOSITORIES: GEO
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Project description:Response to immune checkpoint inhibitors may be improved through combinations with each other and other therapies, raising questions about non-redundancy and resistance. We report results from parallel studies of melanoma patients and mice treated with anti-CTLA4 and radiation (RT). Although combined treatment improved responses, resistance was common. Computational analyses of immune and transcriptomic profiles (provided here) revealed that resistance in mice was due to upregulation of tumor PD-L1 that drives T cell exhaustion. Accordingly, optimal response requires RT, anti-CTLA4, and anti-PD-L1. Anti-CTLA4 inhibits Tregs, RT diversifies and shapes the TCR repertoire, and anti-PD-L1 reinvigorates exhausted T cells. Together, all three therapies promote the expansion of clonotypes with distinct TCR traits. Similar to mice, patients with melanoma showing high PD-L1 did not respond to RT + anti-CTLA4, demonstrated persistent T cell exhaustion, and rapidly progressed. Thus, the combination of RT, anti-CTLA4, and anti-PD-L1 promotes response through distinct mechanisms.
2015-03-16 | GSE65503 | GEO
Project description:We report changes in B cells in patients treated with combination immune checkpoint blockade (CCB; anti-CTLA4 and anti-PD1)
2017-11-29 | GSE104600 | GEO
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
Project description:Corticosteroid premedication and the antitumor effect of immune checkpoint blockade in murine hepatocellular carcinoma models
| PRJNA1185246 | ENA
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 | GSE244982 | GEO
Project description:Immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 are essential components of the cancer therapeutic armamentarium. The remarkable responses seen with ICIs however, are also accompanied by immune-related adverse events (irAEs). These inflammatory side-effects impact virtually all organ systems, with the most common being the skin and gastrointestinal tract. Here, we establish a mouse model of commensal bacteria-driven skin irAEs and demonstrate that immune checkpoint blockade aberrantly unleashes commensal-specific T cell responses. Such responses caused widespread immune cell infiltration and inflammation throughout the skin, recapitulating the skin irAEs seen in patients treated with ICIs. This skin inflammation was dependent on production of the cytokine IL-17 by commensal-specific T cells, which in turn induced hyperactive responses from macrophages and myeloid cells. Importantly, these responses had long-term consequences, with commensal-specific T cells elicited in the context of ICIs being highly sensitive to re-activation by commensals months later. Together, our results establish a mouse model of skin irAEs and show that immune checkpoint blockade can potentiate aberrant immunity to skin commensals with long-lasting consequences.
2022-06-20 | GSE176030 | GEO
Project description:Immune checkpoint blockade (ICB) has demonstrated significant promise for the treatment of advanced malignancies. Anti-CTLA4 and ant-PD1 therapy can activate the immune system and result in durable control in diseases such as melanoma and non-small cell lung cancer.
2018-01-23 | GSE91061 | GEO
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
Project description:PD-1 is an essential inhibitory receptor in T cells, and antibodies that block its interaction with its ligands can augment anti-tumor immune responses. The clinical potential of these agents is limited by the fact that approximately half of all patients who receive anti-PD-1 treatment subsequently develop immune-related Adverse Events (irAEs). To generate insights into the cellular and molecular changes that occur during anti-PD-1 treatment, and to discover predictive biomarkers of irAEs, we performed single cell RNA sequencing of circulating T cells collected from cancer patients who did and did not develop irAEs following PD-1 blockade. Using the K-nearest-neighbor-based network graph drawing layout, we show the involvement of unique gene expression signatures and subpopulations of T cells. We identified that at baseline, patients with arthritis had significantly less cells with features of CD8 TCM cells, patients with pneumonitis had more CD4 TH2 cells, and patients with thyroiditis had more CD4 TH17 cells, when compared to patients who did not develop irAEs. Moreover, T cell receptor sequencing revealed distinctive clonal expansion, and suggested involvement of organ-specific and potentially pathogenic T cell clones among patients with irAEs. Altogether, these data support the hypothesis that different populations of T cells are associated with different irAEs and that quantification and characterization of these populations of T cells pre-treatment could serve as a toxicity-specific, predictive biomarker.
2022-12-14 | GSE216329 | GEO
Project description:<p>Although immune checkpoint blockade (CPB) leads to prolonged responses in 15-40% of patients with metastatic melanoma, treatment refractory disease and progression after initial response remain major causes of mortality. While predictors of response have been reported, the common mechanisms of both primary and acquired resistance are poorly understood. To identify mechanisms of resistance and examine the evolving landscape in response to CPB, we performed whole exome sequencing (WES), immunohistochemistry (IHC), and RNA-sequencing (RNAseq) of longitudinal tumor biopsies from 17 metastatic melanoma patients treated with various CPB therapies. We found no significant changes in both mutational and neoantigen loads over time between responders and nonresponders. However, we identified abnormalities in one gene, beta-2-microglobulin (<i>B2M</i>), an essential component of MHC Class I antigen presentation, that were present in samples during disease progression but not regression. In total, we identified <i>B2M</i> aberrations in 29.4% of patients, including multiple early frameshift mutations, loss of heterozygosity (LOH) overlapping <i>B2M</i>, and absence of tumor-specific <i>B2M</i> protein expression. Additional defects in the antigen presentation and IFNγ pathways were identified but were not restricted to progressing lesions in our cohort. In two independent cohorts of 105 and 38 melanoma patients treated with ipilimumab (anti-CTLA4) and pembrolizumab (anti-PD1) respectively, we found that <i>B2M</i> LOH was enriched 3-fold in nonresponders (~30%) vs. responders (~10%) and associated with poorer overall survival (log-rank p=0.01, p=0.006). Loss of both copies of <i>B2M</i> was found only in nonresponders. We also found evidence for association of LOH overlapping <i>IFNGR1</i> with poorer overall survival exclusively in the anti-PD1 cohort. Thus, <i>B2M</i> loss is likely a common mechanism of primary and acquired resistance to therapies targeting CTLA4 or PD-1.</p>
| phs001427 | dbGaP