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CDK4/6i enhances the antitumor effect of PD1 antibody by promoting TLS formation in ovarian cancer

ABSTRACT: Ovarian cancer is insensitive to immunotherapy and has a high mortality rate. CDK4/6 inhibitors (CDK4/6i) regulate the tumor microenvironment and play an antitumor role. Our previous research demonstrated that lymphocyte aggregation (tertiary lymphoid structures, TLS) was observed after CDK4/6i treatment. This may explain the synergistic action of CDK4/6i with the anti-PD1 antibody. However, the key mechanism by which CDK4/6i promotes TLS formation has not been elucidated. We examine the link between TLS and prognosis. Animal models and high-throughput sequencing were used to explore the potential mechanism by which CDK4/6i promotes TLS formation. Our results showed the presence of TLSs was associated with a favorable prognosis for ovarian cancer. CDK4/6i promoted TLS formation and enhanced the immunotherapeutic effect of the anti-PD1 antibody. The potential mechanism of CDK4/6i affecting the formation of TLS may be through modulating SCD1 and its regulatory molecules ATF3 and CCL4. Our findings provide a theoretical basis for the application of CDK4/6i in ovarian cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE234106 | GEO | 2023/10/12

REPOSITORIES: GEO

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Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders

Project description:CDK4/6 inhibitors (CDK4/6i) are effective in metastatic breast cancer, but they have been only modestly effective in most other tumor types. Here we show that tumors expressing low CDK6 rely on CDK4 function, and are exquisitely sensitive to CDK4/6i. In contrast, tumor cells expressing both CDK4 and CDK6 have increased reliance on CDK6 to ensure cell cycle progression. We discovered that CDK4/6i and CDK4/6 degraders potently bind and inhibit CDK6 selectively in tumors in which CDK6 is highly thermo-unstable and strongly associated with the HSP90/CDC37 complex. In contrast, CDK4/6i and CDK4/6 degraders are ineffective in antagonizing tumor cells expressing thermostable CDK6, due to their weaker binding to CDK6 in these cells. Thus, we uncover a general mechanism of intrinsic resistance to CDK4/6i and CDK4/6i-derived degraders and the need for novel inhibitors targeting the CDK4/6i-resistant, thermostable form of CDK6 for application as cancer therapeutics.

2022-02-16 | PXD023137 | Pride

Tertiary Lymphoid Structure Raises Survival and Immunotherapy in HPV- HNSCC

Project description:The presence of B cells in tumors have been recently reported to predict the better prognosis of patients with cancer. B cells were found primarily in so-called tertiary lymphoid structures (TLSs) in tumor. TLSs are ectopic lymphoid aggregates that form at sites of micro-secondary lymphoid organs, including a B cell follicle with a network of follicular dendritic cells (FDCs) surrounded by T cell zone composed of CD4+ T follicular helper (Tfh) cells and CD8+ T cells and high endothelial venules (HEVs). The presence of TLS is associated with positive outcomes in several human malignancie and More importantly, TLSs enriched in B cells have been proven beneficial for response to ICB in multiple types of cancer. Here, we establish tobacco-associated HNSCC mouse model with TLS enrichment by overexpression of LIGHT in tumor to evaluate the TLS influence in HPV- HNSCC and immunotherapy in HPV- HNSCC.

2022-03-03 | GSE197559 | GEO

CDK4 phosphorylation status and rational use for combining CDK4/6 and BRAF/MEK inhibition in advanced thyroid carcinomas

Project description:Despite overall good prognosis associated to thyroid cancer, poorly differentiated carcinomas (PDTC) and anaplastic carcinomas (ATC) represent major clinical challenges. We have shown that the presence of active T172-phosphorylated CDK4 predicts sensitivity to CDK4/6 inhibitory drugs (CDK4/6i) including palbociclib. Here, CDK4 phosphorylation was detected in all well-differentiated thyoid carcinomas (n=29), 19/20 PDTC, 16/23 ATC, and 18/21 thyroid cancer cell lines including 11 ATC-derived ones. The cell lines lacking CDK4 phosphorylation were insensitive to CDK4/6i. RNA-sequencing and immunohistochemistry revealed that tumors and cell lines without phosphorylated CDK4 presented very high p16CDKN2A levels that were associated with proliferative activity. One of the main mechanisms of resistance to CDK4/6i is RB1 defects or inactivation. RB1 mutations were present in the 3 insensitive cell lines but were not found in 5 of the 7 tumors without phosphorylated CDK4. p16/KI67 immunohistochemistry and a previously developed 11-gene signature identified the likely insensitive tumors and cell lines lacking CDK4 phosphorylation. In cell lines, palbociclib synergized with dabrafenib/trametinib, completely and irreversibly arresting proliferation. The combined drugs prevented resistance mechanisms induced by palbociclib, most notably Cyclin E1-CDK2 activation and a paradoxical stabilization of phosphorylated CDK4 complexes. Our study supports the evaluation of CDK4/6i for ATC/PDTC treatment, including in combination with MEK/BRAF inhibitors.

2023-10-10 | GSE235468 | GEO

FOXA1 phosphorylation by CDK4 prevents activation of novel chromatin regions and HER2 expression in breast cancer

Project description:Cyclin Dependent Kinase 4/6 inhibitors induce transcription in breast tumors via FOXA1 chromatin binding. The use of Cyclin Dependent Kinase 4/6 inhibitors (CDK4/6i) induce transcription in breast tumors. The control mechanism of such genomic changes and their physiological relevance are not elucidated yet. Now, we identified chromatin activation of tumors treated with CDK4/6i. These chromatin changes induce an increase of HER2 expression and signaling. Mechanically, our study demonstrates that FOXA1 is a new substrate of CDK4 and that its phosphorylation limits the binding of FOXA1 to conventional chromatin regions. Moreover, when patients are treated with CDK4/6i, a dephosphorylated FOXA1 binds to additional chromatin regions. By doing so, FOXA1 leads to an increase of HER2 expression and of the activation of HER2-MEK-ERK pathway in breast cancer patients. Accordingly, we might envision a clinical benefit of adding antiHER2 therapy to delay development of resistance and therefore, to prolong PFS in patients yet receiving CDK4/6i.

2023-09-01 | GSE231544 | GEO

CREBBP is a novel tumour suppressor in solid tumours

Project description:The contribution of the majority of frequently mutated genes to tumourigenesis is not fully defined. Many aggressive human cancers, such as triple negative breast cancers (TNBCs), have a poor prognosis and lack tractable biomarkers and targeted therapeutic options. Here, we systematically characterize loss-of-function mutations to generate a functional map of novel driver genes in a 3-dimensional model of breast cancer heterogeneity that more readily recapitulates the unfavourable tumour microenvironment in vivo. This identified the histone acetyltransferase CREBBP as a potent tumour suppressor gene whose silencing provided a 3D-specific growth advantage only under oxygen and nutrient deplete conditions. CREBBP protein expression was altered in a substantial proportion of TNBCs as well as several other solid tumours, including endometrial, bladder, ovarian and squamous lung cancers. In multiple primary tumours and cell models, loss of CREBBP activity resulted in upregulation of the FOXM1 transcriptional network. Strikingly, treatment with a range of CDK4/6 inhibitors (CDK4/6i), that indirectly target FOXM1 activity, selectively impaired growth in both CREBBP-altered spheroids and cell line xenografts and patient derived models from multiple tumour types. This study is the first to provide rationale for CREBBP as a biomarker for CDK4/6i response in cancer representing a new treatment paradigm for tumours that harbour CREBBP alterations that have limited therapeutic options.

2022-03-23 | PXD012098 | Pride

RANK expression and Luminal BC response to CDK4/6 inhibitors

Project description:The combination of endocrine therapy (ET) with CDK4/6 inhibitors (CDK4/6i) was the most recent life-changing hallmark in metastatic Luminal breast cancer (BC). However, intrinsic and acquired resistance affect long-term efficacy. Here, we studied the role of receptor activator of nuclear factor-kB (RANK) pathway in CDK4/6i resistance. We found that RANK overexpression in Luminal BC associates with intrinsic resistance to CDK4/6i, both in vitro and in mouse xenografts. Transcriptomic analysis of mouse tumors highlighted decreased proliferation rate and chronic interferon (IFN)-response as resistance drivers.

2023-06-09 | GSE224435 | GEO

Short term (16 hour) treatment of ER+ breast cancer cell lines with low doses of CDK4/6 inhibition

Project description:Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have improved progression free survival for metastatic, estrogen receptor positive (ER+) breast cancers, but their role in the non-metastatic setting remains unclear. We sought to understand the effects of CDK4/6 inhibition (CDK4/6i) and radiation (RT) in multiple preclinical breast cancer models. Transcriptomic and proteomic analyses were used to identify significantly altered pathways after CDK4/6i. Clonogenic assays were used to quantify the RT enhancement ratio (rER). DNA damage was quantified using γH2AX staining and the neutral comet assay. DNA repair was assessed using RAD51 foci formation and non-homologous end joining (NHEJ) reporter assays. Orthotopic xenografts were used to assess the efficacy of combination therapy. Palbociclib significantly radiosensitized multiple ER+ cell lines at low nanomolar, sub IC50 concentrations (rER: 1.21 – 1.52) and led to a decrease in the surviving fraction of cells at 2 Gy (p < 0.001). Similar results were observed in ribociclib- (rER: 1.08 - 1.68) and abemaciclib-treated (rER: 1.19 - 2.05) cells. Combination treatment decreased RAD51 foci formation (p < 0.001), leading to a suppression of HR activity, but did not affect NHEJ efficiency (p > 0.05). Immortalized breast epithelial cells and cells with acquired resistance to CDK4/6i did not demonstrate radiosensitization (rER: 0.94 – 1.11) or changes in RAD51 foci. In xenograft models, concurrent palbociclib and RT led to a significant decrease in tumor growth. These studies provide preclinical rationale to test CDK4/6i + RT in women with locally-advanced ER+ breast cancer at high risk for locoregional recurrence.

2020-09-24 | GSE155570 | GEO

TLS ChIP-chip

Project description:ChIP using anti-TLS antibody and control to examine binding sites.

2012-03-15 | E-MEXP-3568 | biostudies-arrayexpress

Single-cell profiling of tumor-infiltrating TCF7+ T cells reveals a T lymphocyte subset associated with tertiary lymphoid structures and superior prognosis in oral cancer

Project description:We isolated OSCC cells and performed single-cell RNA sequencing(scRNA-seq). Using immunohistochemistry(IHC) to analyze the relationship between TLS and prognosis. Multiple immunohistochemistry (MIHC), Flow cytometry (FCM) and Spatial analysis were used to verify the characteristics of TCF7+ T cells and their correlation with TLS. The prognostic significance, upstream regulatory network and intercellular communication of the TCF7+ T cell subpopulation were performed by multivariate analysis, Scenic and CellPhone software package analysis.We found a strong association between TCF7+ T cell subsets, TLSs and prognosis. The results suggested that TCF7+ T cells are expressing high levels of TLS-related genes and low levels of immune checkpoint molecules. Finally, we found that TCF7+ T cells were significantly associated with favorable outcomes. We also describe the upstream drivers and intercellular molecules that these cells rely on.The results showed that TCF7+ T cells could be used as a new therapeutic target to regulate the immune response of OSCC and are expected to be a new prognostic marker.

2021-08-13 | GSE172577 | GEO

Efficacy of abemaciclib in palbociclib-resistant hormone receptor positive organoids derived from patient derived xenografts from patients who progressed on palbociclib

Project description:Resistance to CDK4/6 inhibitors plus endocrine therapy, standard of care for HR+/HER2-neg metastatic breast cancer (MBC) patients, remains as a clinical problem with limited therapeutic options after disease progression. Treatment with abemaciclib after progression on a prior CDK4/6i has received increasing interest. However, molecular predictors of cross-resistance and unique mechanism of resistance to each CDK4/6i are unknown. In this study, multiomics analyses revealed ≥30 differentially altered pathways between palbociclib and abemaciclib resistant models. Mechanistic, preclinical and retrospective clinical evidence showed that HR+/HER2-neg MBC tumors refractory to palbociclib still may be responsive to abemaciclib. Based on the unique mechanisms of resistance to each CDK4/6i, we propose that patients who would benefit from abemaciclib treatment post progression on palbociclib could be selected based on the Hallmark gene set enrichment of G2/M pathway, while those who most probably would be refractory could be identified base on the gene set enrichment of OXPHOS pathway.

2023-07-10 | GSE229146 | GEO

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