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PD-1 blockade and CDK4/6 inhibition augment nonoverlapping features of T cell activation in metastatic cancer

ABSTRACT: PD-1 blockade and CDK4/6 inhibition augment nonoverlapping features of T cell activation in metastatic cancer

PROVIDER: PRJNA846618 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19573000_1.fastq.gz	Fastqsanger.gz
	SRR19573000_2.fastq.gz	Fastqsanger.gz
	SRR19573001_1.fastq.gz	Fastqsanger.gz
	SRR19573001_2.fastq.gz	Fastqsanger.gz
	SRR19573002_1.fastq.gz	Fastqsanger.gz

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PD-1 blockade and CDK4/6 inhibition augment nonoverlapping features of T cell activation in metastatic cancer

Project description:We performed single-cell RNA-sequencing and T-cell receptor clonotype tracking of breast and ovarian cancer patients treated with the CDK4/6 inhibitor ribociclib and PD-1 blockade. We identified evidence of two orthogonal treatment-associated phenomena: expansion of T cell effector populations and promotion of T cell memory formation.

2023-01-14 | GSE205589 | GEO

PD-1 blockade and CDK4/6 inhibition augment nonoverlapping features of T cell activation in cancer.

Project description:We performed single-cell RNA-sequencing and T cell receptor clonotype tracking of breast and ovarian cancer patients treated with the CDK4/6 inhibitor ribociclib and PD-1 blockade. We highlight evidence of two orthogonal treatment-associated phenomena: expansion of T cell effector populations and promotion of T cell memory formation. Augmentation of the antitumor memory pool by ribociclib boosts the efficacy of subsequent PD-1 blockade in mouse models of melanoma and breast cancer, pointing toward sequential therapy as a potentially safe and synergistic strategy in patients.

| S-EPMC9884581 | biostudies-literature

CDK4/6-MEK inhibition in MPNSTs causes plasma cell infiltration, sensitization to PD-L1 blockade, and tumor regression

Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are lethal, Ras-driven sarcomas that lack effective therapies. Ras effectors, CDK4/6 and MEK, were identified as rational targets for combination therapy from patient tumor analyses and preclinical drug studies. In MPNST cells, low-dose combinations of CDK4/6 and MEK inhibitors synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death, and decreased clonogenic survival. In immune-deficient mice, dual CDK4/6-MEK inhibition slowed growth but did not shrink MPNSTs in 4 of 5 patient-derived xenografts (PDXs). By comparison, combination therapy of de novo MPNSTs in immunocompetent mice caused tumors to regress, delayed resistant tumor outgrowth, and improved survival relative to monotherapies. While drug-resistant tumors adopted an immunosuppressive microenvironment enriched with MHC II-low macrophages, drug-sensitive tumors that regressed contained plasma cells and increased T cell clustering. In other cancers, intratumoral plasma cells are associated with better response to immune checkpoint blockade (ICB). Impressively, CDK4/6-MEK inhibition sensitized MPNSTs to anti-PD-L1 ICB therapy with some mice displaying complete tumor ablation. These results reveal a novel plasma cell-associated immune response and extended antitumor activity of combined CDK4/6-MEK inhibition in MPNSTs, which dramatically enhanced the efficacy of ICB therapy. This work highlights promising, potentially curative treatment options for MPNSTs.

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CDK4/6 inhibitors reverse primary resistance to anti-PD-1 therapy in LKB1-deficient lung adenocarcinoma

Project description:LKB1 deficiency in lung adenocarcinoma (LUAD) leads to primary resistance to immune checkpoint inhibitors. However, the underlying molecular mechanism remains unclear. Here, we showed that LKB1 deficiency significantly affected the tumor immune landscape by decreasing the infiltration of most immunocyte populations and downregulating the expression of intercellular adhesion molecule-1 (ICAM1). LKB1 deficiency promoted cancer evasion due to loss of ICAM1-mediated antitumor immunity, including immune-competent cell cytotoxicity and tumor infiltration. CDK4/6 inhibitors reversed this process in a targeted manner. A tailored combination strategy using CDK4/6 inhibitors and anti-PD-1 antibodies slowed tumor growth and increased survival in syngeneic mouse models of LKB1-deficient lung adenocarcinoma. Combining a CDK4/6 inhibitor, which is clinically approved, with PD-1 blockade therapy is thus a promising option for lung adenocarcinoma patients harboring LKB1 mutations.

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CDK4/6-MEK inhibition in MPNSTs causes plasma cell infiltration, sensitization to PD-L1 blockade, and tumor regression

Project description:CDK4/6-MEK inhibition in MPNSTs causes plasma cell infiltration, sensitization to PD-L1 blockade, and tumor regression

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Project description:By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. Induction of prolonged early-G1 arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G1 and prevents expression of genes programmed for other cell cycle phases. S-phase synchronization upon removal of the early-G1 block (pG1-S) fails to completely restore scheduled gene expression. Consequently, coordinate loss of IRF4 and gain of Bim and Noxa expression sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 and more profoundly in pG1-S in vitro. Induction of pG1 and pG1-S by CDK4/CDK6 inhibition augments tumor-specific bortezomib killing in myeloma xenografts. Inhibition of CDK4/CDK6 in combination therapy thus represents a novel mechanism-based cancer therapy. PD 0332991 (PD) is the only known specific and reversible CDK4/CDK6 inhibitor. Gene expression was measured in myeloma MM1.S cells treated with PD (0.25 uM) in triplicate for 12, 24 or 36 h, or in cells released from G1, induced by 24hPD, for 4 or 18 h.

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Gene expression profiling of HepG2 cells after treatment of PD-0332991 and CDK4-6 Knockdown

Project description:The aim of this study is to estimate gene expression variations involved in glucose meatbolism in HepG2 cell line after cell cycle(G1 to S phase) inhibition by using drug(PD-0332991) or CDK4-6-knock down. We hypothesized that transition of glycolytic gene expression might indicates the effect of PD-0332991 drug treatment in Hepatocellular carcinoma cells.

2020-02-18 | GSE145389 | GEO

CDK4/6 inhibition suppresses p73 phosphorylation and activates DR5 to potentiate chemotherapy and immune checkpoint blockade

Project description:Targeting cyclin-dependent kinases 4 and 6 (CDK4/6) is a successful therapeutic approach against breast and other solid tumors. Inhibition of CDK4/6 halts cell cycle progression and promotes antitumor immunity. However, the mechanisms underlying the antitumor activity of CDK4/6 inhibitors are not fully understood. We found that CDK4/6 bind and phosphorylate the p53 family member p73 at threonine 86, which sequesters p73 in the cytoplasm. Inhibition of CDK4/6 led to dephosphorylation and nuclear translocation of p73, which transcriptionally activated death receptor 5 (DR5), a cytokine receptor and key component of the extrinsic apoptotic pathway. p73-mediated induction of DR5 by CDK4/6 inhibitors promoted immunogenic cell death (ICD) of cancer cells. Deletion of DR5 in cancer cells in vitro and in vivo abrogated the potentiating effects of CDK4/6 inhibitors on immune cytokine TNF-related apoptosis-inducing ligand (TRAIL), 5-fluorouracil (5-FU) chemotherapy, and anti-PD-1 immunotherapy. Together, these results reveal a previously unrecognized consequence of CDK4/6 inhibition, which may be critical for potentiating the killing and immunogenic effects on cancer cells.

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Blockade of IL-1b and PD-1 with combination chemotherapy reduces systemic myeloid suppression in metastatic pancreatic cancer with heterogeneous effects in the tumor

Project description:Clinical and translational results from a phase Ib trial testing whether IL-1β blockade in human pancreatic cancer would alleviate myeloid immunosuppression and reveal anti-tumor T cell responses to PD-1 blockade.

2024-07-01 | GSE267814 | GEO

Single-cell RNAseq of α-PD-1 relapsing YUMM2.1 tumours subsequently treated with PARP14i in vivo

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