RNA-seq analysis of isogenic mouse prostate cancer cell lines with distinct sensitivity to immune checkpoint therapy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE252986 | GEO | 2024/02/13
REPOSITORIES: GEO
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Project description:Solid tumours are highly refractory to immune checkpoint blockade (ICB) therapies due to the functional impairment of effector T cells and their inefficient trafficking to tumours. T-cell activation is negatively regulated by C-terminal Src kinase (CSK); however, the exact mechanism remains unknown. Here we show that the conserved oncogenic tyrosine kinase Activated CDC42 kinase 1 (ACK1) is able to phosphorylate CSK at Tyrosine 18 (pY18), which enhances CSK function, constraining T-cell activation. Mice deficient in the Tnk2 gene encoding Ack1, are characterized by diminished CSK pY18 phosphorylation and spontaneous activation of CD8+ and CD4+ T cells, resulting in inhibited growth of transplanted ICB-resistant tumours. Furthermore, ICB treatment of castration-resistant prostate cancer (CRPC) patients results in re-activation of ACK1/pY18-CSK signalling, confirming the involvement of this pathway in ICB insensitivity. An ACK1 small-molecule inhibitor, (R)-9b, recapitulates inhibition of ICB-resistant tumours, which provides evidence for ACK1 enzymatic activity playing a pivotal role in generating ICB resistance. Overall, our study identifies an important mechanism of ICB resistance and holds potential for expanding the scope of ICB therapy to tumours that are currently unresponsive.
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Project description:Methodologies for untargeted metabolomic profiling using liquid chromatography-mass spectrometry (LC-MS) were developed and applied to lipid-depleted methanolic extracts of soybeans seeds obtained from four near isogenic soybean lines (NILs) that differed in phytate content. The four lines differed in mutations for genes encoding two highly homologous multi-drug resistant proteins (MRPs). The double mutant exhibited the low phytate/emergence phenotype whereas the other three NILs, namely the two single mutants and the wild type, did not. Lipid-depleted aqueous methanol extracts were analyzed by orthogonal chromatographic separations (reversed-phase and hydrophilic interaction) in both positive and negative ionization modes. Principal component analysis (PCA) of the LC-MS data clearly separated the low phytate line from the other three, with the major metabolite differences residing in the soyasaponin composition. Group A soyasaponins containing C22-terminated acetylated glucosides were of much lower concentration in the low phytate line, which favored terminally acetylated xyloside-based soyasaponins (soyasaponin A4, A5 and A6). Differing levels of the allergen Gly m 1 were also detected.
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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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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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Project description:Although multiple studies have investigated the biomarkers of response to immune checkpoint blockade (ICB), the significance of each biomarker varies across clinical cohorts independent of cancer type. It remains unclear whether primary ICB response and resistance is encoded in the cancer cells (cancer-intrinsic) or driven by the immune microenvironment unique to each host (cancer-extrinsic). To answer this question, we established a unique mouse system that utilizes clonal tracing and mathematical modeling to uncouple the cancer-intrinsic and -extrinsic mechanisms of ICB resistance. We found that tumors with the same clonal constitution show heterogeneous ICB response in different hosts. Primary resistance is associated with the cancer-extrinsic immune microenvironment rather than proliferation of intrinsically ICB-resistant cancer cells. Instead, pre-existing cancer-intrinsic ICB-resistant clones with distinct transcriptional and epigenetic profiles were enriched in responders. We further identified two gene expression signatures associated with cancer-intrinsic resistance, including increased interferon response genes and glucocorticoid response genes. Our findings are supported by experiments in another mouse model and clinical data from multiple ICB treatment cohorts. Our study emphasizes the importance of optimal microenvironment in cancer immunotherapy, and implicates the value of immunotherapy biomarkers that account for both cancer-intrinsic and -extrinsic mechanisms of resistance.
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Project description:Although multiple studies have investigated the biomarkers of response to immune checkpoint blockade (ICB), the significance of each biomarker varies across clinical cohorts independent of cancer type. It remains unclear whether primary ICB response and resistance is encoded in the cancer cells (cancer-intrinsic) or driven by the immune microenvironment unique to each host (cancer-extrinsic). To answer this question, we established a unique mouse system that utilizes clonal tracing and mathematical modeling to uncouple the cancer-intrinsic and -extrinsic mechanisms of ICB resistance. We found that tumors with the same clonal constitution show heterogeneous ICB response in different hosts. Primary resistance is associated with the cancer-extrinsic immune microenvironment rather than proliferation of intrinsically ICB-resistant cancer cells. Instead, pre-existing cancer-intrinsic ICB-resistant clones with distinct transcriptional and epigenetic profiles were enriched in responders. We further identified two gene expression signatures associated with cancer-intrinsic resistance, including increased interferon response genes and glucocorticoid response genes. Our findings are supported by experiments in another mouse model and clinical data from multiple ICB treatment cohorts. Our study emphasizes the importance of optimal microenvironment in cancer immunotherapy, and implicates the value of immunotherapy biomarkers that account for both cancer-intrinsic and -extrinsic mechanisms of resistance.
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Project description:Although multiple studies have investigated the biomarkers of response to immune checkpoint blockade (ICB), the significance of each biomarker varies across clinical cohorts independent of cancer type. It remains unclear whether primary ICB response and resistance is encoded in the cancer cells (cancer-intrinsic) or driven by the immune microenvironment unique to each host (cancer-extrinsic). To answer this question, we established a unique mouse system that utilizes clonal tracing and mathematical modeling to uncouple the cancer-intrinsic and -extrinsic mechanisms of ICB resistance. We found that tumors with the same clonal constitution show heterogeneous ICB response in different hosts. Primary resistance is associated with the cancer-extrinsic immune microenvironment rather than proliferation of intrinsically ICB-resistant cancer cells. Instead, pre-existing cancer-intrinsic ICB-resistant clones with distinct transcriptional and epigenetic profiles were enriched in responders. We further identified two gene expression signatures associated with cancer-intrinsic resistance, including increased interferon response genes and glucocorticoid response genes. Our findings are supported by experiments in another mouse model and clinical data from multiple ICB treatment cohorts. Our study emphasizes the importance of optimal microenvironment in cancer immunotherapy, and implicates the value of immunotherapy biomarkers that account for both cancer-intrinsic and -extrinsic mechanisms of resistance.
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