scholarly journals 614 Investigating immune mediated mechanisms of PARPi resistance in BRCA1-associated triple negative breast cancer (TNBC)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A644-A644
Author(s):  
Anita Mehta ◽  
Madeline Townsend ◽  
Madisson Oliwa ◽  
Patrice Lee ◽  
Nicholas Saccomano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
Immune Response ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Triple Combination ◽  
Tumor Clearance ◽  
Sting Pathway

BackgroundPoly(ADP-ribose) polymerase inhibitors (PARPi) have improved the outcomes of BRCA-associated breast cancer; however, treatment responses are often not durable. Our preclinical studies demonstrated that PARPi activates the cGAS/STING pathway and recruitment of anti-tumor CD8+ T-cells that are required for tumor clearance [1]. These studies contributed to development of clinical trials testing PARPi plus immune checkpoint blockade (ICB). Unfortunately, early phase trials of PARPi + ICB have not yet suggested efficacy will be superior to PARPi monotherapy. Lack of demonstrated clinical synergy between PARPi + ICB underscores the need to study the tumor microenvironment (TME) during PARPi therapy to identify optimal strategies to enhance T-cell activation. We recently showed that PARPi induces CSF-1R+ suppressive tumor associated macrophages (TAMs) that restrict antitumor immune responses, contributing to PARPi resistance [2]. Removing TAMs with anti-CSF-1R therapy in combination with PARPi significantly enhanced overall survival (OS) compared to PARPi monotherapy in preclinical models [2]. Here, we investigate how modulating TAMs can enhance PARPi + ICB.MethodsMice bearing BRCA1-deficient TNBC (K14-Cre;Brca1f/f;p53f/f) tumors were treated for 98 days with PARPi (Talazoparib) ± small molecule inhibitor of CSF-1R (ARRAY-382; CSF-1Ri) ± anti-PD-1 and then followed for survival. Flow cytometry was employed to elucidate changes in the TME after treatment.ResultsPARPi conferred a significant survival advantage over vehicle treated mice (median OS 33 v. 14 days; p=0.0034) and 2/8 PARPi-treated mice experienced complete tumor clearance at day 98. PARPi + CSF-1Ri treated mice (median OS 140 days) remarkably cleared 7/10 tumors by day 98. The addition of anti-PD-1 to PARPi did not enhance OS compared to PARPi monotherapy. The triple combination of anti-PD-1 + PARPi + CSF-1Ri has not yet significantly enhanced the median OS compared to PARPi + CSF-1Ri (ongoing; 168 v. 140 days); nor did it increase clearance of tumor by day 98 (7/10). However, the triple combination led to superior long term tumor clearance. At day 161 the triple combination exhibited 5/10 tumor free mice compared to 2/10 treated with PARPi + CSF-1Ri. To elucidate how CSR-1Ri enhanced PARPi + ICB responses, flow cytometry was performed and revealed increased expression of the co-stimulatory molecule CD80, reduced tissue resident macrophages (CX3CR1+) and lower CSF-1R expression compared to PARPi + ICB.ConclusionsThese data suggest that targeting immunosuppressive macrophages may induce a favorable anti-tumor immune response and enhance responses to PARPi plus ICB. We are currently evaluating the adaptive immune response in this context.ReferencesPantelidou, C., et al., PARP inhibitor efficacy depends on CD8+ T cell recruitment via intratumoral STING pathway activation in BRCA-deficient models of triple-negative breast cancer. Cancer Discovery, 2019: p. CD-18-1218.Mehta, A.K., et al., Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer. Nat Cancer, 2021. 2(1): p. 66–82.

scholarly journals PARP Inhibitor Efficacy Depends on CD8+ T-cell Recruitment via Intratumoral STING Pathway Activation in BRCA-Deficient Models of Triple-Negative Breast Cancer

2019 ◽  
Vol 9 (6) ◽  
pp. 722-737 ◽  
Author(s):  
Constantia Pantelidou ◽  
Olmo Sonzogni ◽  
Mateus De Oliveria Taveira ◽  
Anita K. Mehta ◽  
Aditi Kothari ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Cd8 T Cell ◽  
Cell Recruitment ◽  
Pathway Activation ◽  
Sting Pathway

Effect of metformin on PARP inhibitors-induced epithelial-mesenchymal transition and PD-L1 expression in triple-negative breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1063-1063 ◽  
Author(s):  
Ye Han ◽  
Chia-Wei Li
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Mesenchymal Transition

1063 Background: Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising targeted therapies for BRCA-mutated cancers by blocking repair of DNA double-strand breaks. However, resistance to PARP inhibitors have been described in some patients lowering overall response rates. The mechanisms underlying PARP inhibitor (PARPi) resistance are an area of active investigation. Methods: PARPi adaptive resistant clones (MDA-MB-468, MDA-MB-231, HCC1806) were generated in triple-negative breast cancer cell lines. Through morphologic observation and functional analysis, we evaluated epithelial-mesenchymal transition (EMT) and changes in immune checkpoint programmed death-ligand 1 (PD-L1). We also downregulated the expression of PD-L1 by shRNA to study the role of PD-L1 in PARPi resistance. We evaluated the immunology sensitivity to cytotoxic T cell upon PD-L1 change using a murine ex-vivo CD8+ T cell killing assay and a comparison of total killing cells percentage per well. Results: We demonstrated that inhibition of PARP enhances EMT, which induces phosphorylation of Akt at S473. This in turn upregulates the expression of PD-L1 by 2-3 fold in triple-negative breast cancer cells. In addition, PARPi–induced EMT occurred independent of PD-L1 upregulation in triple-negative breast cancer cells. Metformin administration (10µM) was found to reverse EMT by blocking the p-Akt S473 axis through activation of AMPK, resulting in downregulation of PD-L1 expression and sensitizing PARPi-resistant cancer cells to T cell killing. Conclusions: In summary, we identified that induction of EMT is a new mechanism for PARP inhibitor resistance. Metformin was able to reverse EMT and therefore a combination of metformin and PARP inhibitors may be a promising therapeutic strategy to increase the efficacy of PARP inhibitors and tumor sensitivity to T cells.

scholarly journals Effect of Oxaliplatin, Olaparib and LY294002 in Combination on Triple-Negative Breast Cancer Cells

2021 ◽  
Vol 22 (4) ◽  
pp. 2056
Author(s):  
Kitti Andreidesz ◽  
Balazs Koszegi ◽  
Dominika Kovacs ◽  
Viola Bagone Vantus ◽  
Ferenc Gallyas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Combined Treatment ◽  
Parp Inhibition ◽  
Akt Pathway ◽  
Platinum Compound ◽  
Mcf7 Cells ◽  
Cancer Line

Triple-negative breast cancer (TNBC) has a poor prognosis as the therapy has several limitations, most importantly, treatment resistance. In this study we examined the different responses of triple-negative breast cancer line MDA-MB-231 and hormone receptor-positive breast cancer line MCF7 to a combined treatment including olaparib, a poly-(ADP ribose) polymerase (PARP) inhibitor, oxaliplatin, a third-generation platinum compound and LY294002, an Akt pathway inhibitor. We applied the drugs in a single, therapeutically relevant concentration individually and in all possible combinations, and we assessed the viability, type of cell death, reactive oxygen species production, cell-cycle phases, colony formation and invasive growth. In agreement with the literature, the MDA-MB-231 cells were more treatment resistant than the MCF7 cells. However, and in contrast with the findings of others, we detected no synergistic effect between olaparib and oxaliplatin, and we found that the Akt pathway inhibitor augmented the cytostatic properties of the platinum compound and/or prevented the cytoprotective effects of PARP inhibition. Our results suggest that, at therapeutically relevant concentrations, the cytotoxicity of the platinum compound dominated over that of the PARP inhibitor and the PI3K inhibitor, even though a regression-based model could have indicated an overall synergy at lower and/or higher concentrations.

scholarly journals Pilose antler polypeptides promote chemosensitization and T-cell infiltration of triple-negative breast cancer

2021 ◽  
Vol 85 ◽  
pp. 104664
Author(s):  
Mohan Li ◽  
Kexin Zheng ◽  
Shiliang Ma ◽  
Pengpeng Hu ◽  
Bo Yuan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cell Infiltration ◽  
T Cell Infiltration

scholarly journals Blocking Fra-1 sensitizes triple-negative breast cancer to PARP inhibitor

2021 ◽  
Author(s):  
Dandan Song ◽  
Huan He ◽  
Indranil Sinha ◽  
Linnea Hases ◽  
Feifei Yan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor

The exosomes derived from CAR-T cell efficiently target mesothelin and reduce triple-negative breast cancer growth

2021 ◽  
Vol 360 ◽  
pp. 104262
Author(s):  
Pengxiang Yang ◽  
Xingjian Cao ◽  
Huilong Cai ◽  
Panfeng Feng ◽  
Xiang Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cancer Growth ◽  
Car T Cell ◽  
Car T ◽  
Breast Cancer Growth

scholarly journals Substance P Antagonism as a Novel Therapeutic Option to Enhance Efficacy of Cisplatin in Triple Negative Breast Cancer and Protect PC12 Cells against Cisplatin-Induced Oxidative Stress and Apoptosis

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3871
Author(s):  
Emma Rodriguez ◽  
Guangsheng Pei ◽  
Sang T. Kim ◽  
Alexis German ◽  
Prema Robinson
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
Cell Line ◽  
Pc12 Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Therapeutic Option ◽  
Neuronal Cell ◽  
Receptor Antagonism ◽  
Tnbc Cell

Although cisplatin is very effective as a treatment strategy in triple-negative breast cancer (TNBC), it has unwarranted outcomes owing to recurrence, chemoresistance and neurotoxicity. There is critically important to find new, effective and safe therapeutics for TNBC. We determined if SP-receptor antagonism in combination with cisplatin may serve as a novel, more efficacious and safer therapeutic option than existing therapies for TNBC. We used a neuronal cell line (PC12) and two TNBC cell lines (Sum 185 and Sum 159) for these studies. We determined that the levels of cells expressing the high-affinity SP-receptor (neurokinin 1 receptor (NK1R)), as determined by flow-cytometry was significantly elevated in response to cisplatin in all three cells. We determined that treatment with aprepitant, an SP-receptor antagonist decreased cisplatin-induced, loss of viability (studied by MTT assay), production of reactive oxygen species (by DCFDA assay) and apoptosis (by flow-cytometry) in PC12 cells while it was increased in the two TNBC cells. Furthermore, we demonstrated that important genes associated with metastases, inflammation, chemoresistance and cell cycle progression are attenuated by SP-receptor antagonism in the TNBC cell line, Sum 185. These studies implicate that SP-receptor antagonism in combination with cisplatin may possibly serve as a novel, more efficacious and safer therapeutic option than existing therapies for TNBC.

scholarly journals Deciphering the temporal heterogeneity of cancer-associated fibroblast subpopulations in breast cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Freja Albjerg Venning ◽  
Kamilla Westarp Zornhagen ◽  
Lena Wullkopf ◽  
Jonas Sjölund ◽  
Carmen Rodriguez-Cupello ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Ex Vivo ◽  
Smooth Muscle Actin ◽  
Mammary Tissue ◽  
Temporal Heterogeneity ◽  
Alpha Smooth Muscle Actin ◽  
Murine Tumours

Abstract Background Cancer-associated fibroblasts (CAFs) comprise a heterogeneous population of stromal cells within the tumour microenvironment. CAFs exhibit both tumour-promoting and tumour-suppressing functions, making them exciting targets for improving cancer treatments. Careful isolation, identification, and characterisation of CAF heterogeneity is thus necessary for ex vivo validation and future implementation of CAF-targeted strategies in cancer. Methods Murine 4T1 (metastatic) and 4T07 (poorly/non-metastatic) orthotopic triple negative breast cancer tumours were collected after 7, 14, or 21 days. The tumours were analysed via flow cytometry for the simultaneous expression of six CAF markers: alpha smooth muscle actin (αSMA), fibroblast activation protein alpha (FAPα), platelet derived growth factor receptor alpha and beta (PDGFRα and PDGFRβ), CD26/DPP4 and podoplanin (PDPN). All non-CAFs were excluded from the analysis using a lineage marker cocktail (CD24, CD31, CD45, CD49f, EpCAM, LYVE-1, and TER-119). In total 128 murine tumours and 12 healthy mammary fat pads were analysed. Results We have developed a multicolour flow cytometry strategy based on exclusion of non-CAFs and successfully employed this to explore the temporal heterogeneity of freshly isolated CAFs in the 4T1 and 4T07 mouse models of triple-negative breast cancer. Analysing 128 murine tumours, we identified 5–6 main CAF populations and numerous minor ones based on the analysis of αSMA, FAPα, PDGFRα, PDGFRβ, CD26, and PDPN. All markers showed temporal changes with a distinct switch from primarily PDGFRα+ fibroblasts in healthy mammary tissue to predominantly PDGFRβ+ CAFs in tumours. CD26+ CAFs emerged as a large novel subpopulation, only matched by FAPα+ CAFs in abundance. Conclusion We demonstrate that multiple subpopulations of CAFs co-exist in murine triple negative breast cancer, and that the abundance and dynamics for each marker differ depending on tumour type and time. Our results form the foundation needed to isolate and characterise specific CAF populations, and ultimately provide an opportunity to therapeutically target specific CAF subpopulations.

Sign in / Sign up

Export Citation Format

Share Document