To explore whether a cross-talk exists between PARP inhibition and PD-L1/PD-1 immune checkpoint axis, and determine whether blockade of PD-L1/PD-1 potentiates PARP inhibitor (PARPi) in tumor ...suppression.
Breast cancer cell lines, xenograft tumors, and syngeneic tumors treated with PARPi were assessed for PD-L1 expression by immunoblotting, IHC, and FACS analyses. The phospho-kinase antibody array screen was used to explore the underlying mechanism of PARPi-induced PD-L1 upregulation. The therapeutic efficacy of PARPi alone, PD-L1 blockade alone, or their combination was tested in a syngeneic tumor model. The tumor-infiltrating lymphocytes and tumor cells isolated from syngeneic tumors were analyzed by CyTOF and FACS to evaluate the activity of antitumor immunity in the tumor microenvironment.
PARPi upregulated PD-L1 expression in breast cancer cell lines and animal models. Mechanistically, PARPi inactivated GSK3β, which in turn enhanced PARPi-mediated PD-L1 upregulation. PARPi attenuated anticancer immunity via upregulation of PD-L1, and blockade of PD-L1 resensitized PARPi-treated cancer cells to T-cell killing. The combination of PARPi and anti-PD-L1 therapy compared with each agent alone significantly increased the therapeutic efficacy
Our study demonstrates a cross-talk between PARPi and tumor-associated immunosuppression and provides evidence to support the combination of PARPi and PD-L1 or PD-1 immune checkpoint blockade as a potential therapeutic approach to treat breast cancer.
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Breast cancer is a heterogeneous disease with a complex microenvironment consisting of tumor cells, immune cells, fibroblasts and vascular cells. These cancer-associated cells shape the tumor ...microenvironment (TME) and influence the progression of breast cancer and the therapeutic responses in patients. The exact composition of the intra-tumoral cells is mixed as the highly heterogeneous and dynamic nature of the TME. Recent advances in single-cell technologies such as single-cell DNA sequencing (scDNA-seq), single-cell RNA sequencing (scRNA-seq) and mass cytometry have provided new insights into the phenotypic and functional diversity of tumor-infiltrating cells in breast cancer. In this review, we have outlined the recent progress in single-cell characterization of breast tumor ecosystems, and summarized the phenotypic diversity of intra-tumoral cells and their potential prognostic relevance.
Background We aimed to evaluate the efficacy, safety, and immunogenicity of a SARS-CoV-2 mRNA vaccine (Omicron BA.5) LVRNA012 given as the booster in immunized but SARS-CoV-2 infection-free adults in ...China. Methods This is a single-center, randomized, double-blind, placebo-controlled phase 3 clinical trial enrolling healthy adult participants (≥18 years) who had completed two or three doses of inactivated COVID-19 vaccines at least 6 months before, in Bengbu, Anhui province, China. Eligible participants were randomly assigned (1:1) to receive a booster intramuscular vaccination with an LVRNA012 vaccine (100ug) or placebo. The primary endpoint was the protective efficacy of a booster dose of the LVRNA012 vaccine or placebo against symptomatic COVID-19 of any severity 14 days after vaccination. Laboratory-confirmed COVID-19 infections were identified from 14 days to 180 days after intervention, with active surveillance for symptomatic illness 8 times per month between 7 to 90 days and at least once per month between 90 to 180 days after intervention. Results 2615 participants were recruited and randomly assigned in a 1:1 ratio to either the vaccine group (1308) or the placebo group (1307). A total of 141 individuals (46 in the LVRNA012 group and 95 in the placebo group) developed symptomatic COVID-19 infection 14 days after the booster immunization, showing a vaccine efficacy of 51.9% (95% CI, 31.3% to 66.4%). Most infections were detected 90 days after intervention during a period when XBB was prevalent in the community. Adverse reactions were reported by 64% of participants after the LVRNA012 vaccination, but most of them were mild or moderate. The booster vaccination with the LVRNA012 mRNA vaccine could significantly enhance neutralizing antibody titers against the Omicron variant XBB.1.5 (GMT 132.3 99.8, 175.4) than did those in the placebo group (GMT 12.5 8.4, 18.7) at day 14 for the previously immunized individuals. Conclusion The LVRNA012 mRNA vaccine is immunogenic, and shows robust efficacy in preventing COVID-19 during the omicron-predominate period. Clinical trial registration ClinicalTrials.gov , identifier NCT05745545.
BackgroundSentinel lymph nodes (LNs) are regarded as key immune surveillance sites in cancer wherein mature dendritic cells present tumor-derived antigens to prime and activate T cells, which then ...migrate to the tumor site. However, it is unclear whether the tumor-specific T cells can be elicited within the tumor independent of the sentinel LNs.MethodsWe performed an integrative analysis of gene expression profiles of 65,285 cells and T cell receptor sequences of 15,831 T cells from 5 paired primary breast tumors and sentinel LNs to identify where clonal T cells come from and the characteristics of those clonal T cells.ResultsThe proportion of clonal T cells was higher in the primary tumors compared with the sentinel LNs, whereas all expanded clones identified in the sentinel LN were also present in the primary tumors. In contrast, 10.91% of the expanded clones in the primary tumors were not found in the sentinel LNs. These novel intratumoral T cell clones were characterized by high tissues retention capacity (CXCR6 +ITGAE+) and a distinct coinhibitory pattern (CD39 +NKG2A+) compared with the expanded T cell clones common to both sites. Furthermore, multiplex immunofluorescence imaging showed the presence of tertiary lymphoid structures (TLS) in the primary breast tumors wherein the activated cytolytic T cells were concentrated, indicating its possible role in eliciting non-sentinel LN-derived T cell clones.ConclusionsOur study revealed expanded intratumor non-sentinel LN derived T cell clones located in the TLS, which points to the need for exploring the role of TLS in antitumor immunity.
Our previous studies showed that BikDD, a constitutively active mutant form of Bik, exhibited powerful antitumor effects in preclinical pancreatic, lung and breast cancer models. Howerver, the ...antitumor activity of BikDD in triple-negative breast cancer (TNBC) is unknown. Here we show that aberrant expression of p-ERK1/2 was a meaningful molecular phenotype in TNBC patients, and can be an obstacle for treatment because of the converse correlation with Bik. A novel mutant, BikDDA, in which Ser124 was changed to Alanine to block BikDD phosphorylation by p-ERK1/2 prevented subsequent ubiquitin-proteasome degradation. BikDDA showed a prolonged half-life and enhanced pro-apoptotic ability in TNBC cells compared with BikDD. Moreover, aberrant expression of p-ERK1/2 was associated with 5-fluorouracil resistance in breast cancer patients and BikDDA enhanced the therapeutic effects of 5-fluorouracil in vitro.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Immune checkpoint therapy (ICT) shows encouraging results in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC) but still elicits a sub-optimal response among those ...with bone metastases. Analysis of patients’ bone marrow samples revealed increased Th17 instead of Th1 subsets after ICT. To further evaluate the different tumor microenvironments, we injected mice with prostate tumor cells either subcutaneously or intraosseously. ICT in the subcutaneous CRPC model significantly increases intra-tumoral Th1 subsets and improves survival. However, ICT fails to elicit an anti-tumor response in the bone CRPC model despite an increase in the intra-tumoral CD4 T cells, which are polarized to Th17 rather than Th1 lineage. Mechanistically, tumors in the bone promote osteoclast-mediated bone resorption that releases TGF-β, which restrains Th1 lineage development. Blocking TGF-β along with ICT increases Th1 subsets and promotes clonal expansion of CD8 T cells and subsequent regression of bone CRPC and improves survival.
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•Lack of Th1 cells in the tumor confers resistance to immune checkpoint therapy•High TGF-β amounts in prostate cancer bone metastases restrains the Th1 lineage and hinders ICT•Tumors in the bone promote osteoclast-mediated bone resorption that releases TGF-β•TGF-β inhibition allows Th1 development and augments ICT in bone prostate cancer
The response to immune checkpoint therapy in a subset of patients with castration-resistant prostate cancer who develop bone metastases can be improved by promoting CD4 Th1 effector T cell responses and clonal expansion of CD8 T cells through TGF-β blockade
Existing reports showed loss of Nrdp1, an E3 ubiquitin ligase, promoted breast cancer malignancy because of failure to deregulate ErbB3. However, the correlation between Nrdp1 expression with ...clinical data is still unknown.
We explored the predictive value of Nrdp1 regarding the clinical outcome of patients and the benefit of adjuvant anthracycline-based chemotherapy.
113 primary breast cancer samples were obtained during surgery and the patients received average 10-year follow-up. We obtained Nrdp1 and ErbB3 expressions by immunohistochemistry.
Nrdp1 expression correlates with overall survival and disease-free survival of patients, with a hazard ratio of 0.237 (p=0.001) and 0.280 (p< 0.001) respectively. Additionally Nrdp1 correlates inversely with ErbB3 expression in tumor tissue (p=0.009). However the prognosis of Nrdp1 was not solely dependent on its regulation of ErbB3 degradation since there was also a significant correlation between Nrdp1 and overall survival (p=0.005) in ErbB3-negative patients. In patients who received anthracycline-based chemotherapy, low Nrdp1 expression indicated decreased disease-free survival (p=0.006) and high rates of metastasis and/or recurrence (p<0.001).
Nrdp1 may serve as a useful biomarker for the clinical outcome and efficacy of adjuvant anthracyclines-based chemotherapy in breast cancer.The prognosis of Nrdp1 was not solely dependent on its deregulation of ErbB3.
Inhibitors against poly (ADP-ribose) polymerase (PARP) are promising targeted agents currently used to treat BRCA-mutant ovarian cancer and are in clinical trials for other cancer types, including ...BRCA-mutant breast cancer. To enhance the clinical response to PARP inhibitors (PARPis), understanding the mechanisms underlying PARPi sensitivity is urgently needed. Here, we show enhancer of zeste homolog 2 (EZH2), an enzyme that catalyzes H3 lysine trimethylation and associates with oncogenic function, contributes to PARPi sensitivity in breast cancer cells. Mechanistically, upon oxidative stress or alkylating DNA damage, PARP1 interacts with and attaches poly-ADP-ribose (PAR) chains to EZH2. PARylation of EZH2 by PARP1 then induces PRC2 complex dissociation and EZH2 downregulation, which in turn reduces EZH2-mediated H3 trimethylation. In contrast, inhibition of PARP by PARPi attenuates alkylating DNA damage-induced EZH2 downregulation, thereby promoting EZH2-mediated gene silencing and cancer stem cell property compared with PARPi-untreated cells. Moreover, the addition of an EZH2 inhibitor sensitizes the BRCA-mutant breast cells to PARPi. Thus, these results may provide a rationale for combining PARP and EZH2 inhibition as a therapeutic strategy for BRCA-mutated breast and ovarian cancers.
Abstract
Cellular heterogeneity in the tumor immune microenvironment (TIME) of gastric cancer (GC) is progressively molded in pre- and early-malignant lesions and has a profound impact on disease ...progression and responses to therapeutics, in particular those based on immune checkpoint blockade (ICB). To date, no study has been conducted to characterize the single-cell kinetics of tumor-infiltrating immune populations in gastric cancer patients treated with ICB. Here, we generated for the first time single-cell RNA sequencing (scRNA-seq) and TCR sequencing (scTCR-seq) profiles of ICB-treated primary GC tumors, as well as liver and ovary metastases. When integrated with public scRNA-seq datasets, our data capture a full trajectory of GC malignancy comprising more than 300,000 cells derived from 73 samples. We further performed bulk TCR-seq, cytometry by time of flight (CyTOF), and multiplex immunofluorescence (mxIF) on independent GC samples to orthogonally validate the key observations from the scRNA-seq cohort and unbiasedly search for more in-depth and spatial-relationship-focused features of ICB-responsive immune populations. Built upon this multi-omic atlas of GC cell states, we identified remarkable transformation of the abundance and clonal dynamics of distinct immune populations and their population-specific transcriptional programs. Most importantly, we observed the rejuvenation of exhausted CD8+ T cells induced by anti-PD-1 treatment, which is associated with the enhanced immunogenicity of gastric cancer cells. In addition, we found the enrichment of NK-like terminally differentiated CD8+ T cells in metastases independent of migration destinations. Our single-cell ICB-perturbed spatiotemporal GC landscape reveals how neoadjuvant checkpoint blockade induces local and systemic tumor immunity. As a cellular and molecular reference, it also enables high-resolution interpretation of future single-cell omics data in gastric cancer that may be masked by de novo analysis.
Citation Format: Yikai Luo, Muxing Kang, Wei Liu, Shiping Jiao, Lie Wang, Jian Chen, Han Liang. A spatiotemporal cell atlas of human gastric malignancy reveals mechanisms underlying metastasis and immunotherapy response abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6665.
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