scholarly journals Targeting a cell surface vitamin D receptor on tumor-associated macrophages in triple-negative breast cancer

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Fernanda I Staquicini ◽  
Amin Hajitou ◽  
Wouter HP Driessen ◽  
Bettina Proneth ◽  
Marina Cardó-Vila ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Vitamin D ◽  
Immune Response ◽  
Cell Surface ◽  
Vitamin D Receptor ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Antitumor Immune Response ◽  
Tumor Associated Macrophages ◽  
A Cell

Triple-negative breast cancer (TNBC) is an aggressive tumor with limited treatment options and poor prognosis. We applied the in vivo phage display technology to isolate peptides homing to the immunosuppressive cellular microenvironment of TNBC as a strategy for non-malignant target discovery. We identified a cyclic peptide (CSSTRESAC) that specifically binds to a vitamin D receptor, protein disulfide-isomerase A3 (PDIA3) expressed on the cell surface of tumor-associated macrophages (TAM), and targets breast cancer in syngeneic TNBC, non-TNBC xenograft, and transgenic mouse models. Systemic administration of CSSTRESAC to TNBC-bearing mice shifted the cytokine profile toward an antitumor immune response and delayed tumor growth. Moreover, CSSTRESAC enabled ligand-directed theranostic delivery to tumors and a mathematical model confirmed our experimental findings. Finally, in silico analysis showed PDIA3-expressing TAM in TNBC patients. This work uncovers a functional interplay between a cell surface vitamin D receptor in TAM and antitumor immune response that could be therapeutically exploited.

Dynamic relationship between cycling kinetics of triple-negative breast cancer and tumor infiltrating immune cells.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1100-1100
Author(s):  
Ishita Choudhary ◽  
Sergey Klimov ◽  
Padmashree C.G. Rida ◽  
Angela Ogden ◽  
Andrew R. Green ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
T Cells ◽  
Triple Negative Breast Cancer ◽  
Immune Cells ◽  
Triple Negative ◽  
Antitumor Immune Response ◽  
M2 Macrophage ◽  
Slow Cycling ◽  
Kinetics Of

1100 Background: Recent studies show strong correlation between tumor infiltrating lymphocytes (TILs) and triple-negative breast cancer (TNBC) patient survival. CD8+ T cells serve as a favorable prognostic marker for TNBC. In addition, other cells such as CD4+ T cells, macrophages, B cells, and Tregs also infiltrate tumors. In this study, we delineate a strong relationship between the cycling kinetics of proliferating cells in TNBCs and antitumor immune response. Methods: A multi-institutional study performed by our group has previously shown that KAMS (Ki67-Adjusted Mitotic Score) provides a measure of the cycling kinetics of proliferating tumor cells and robustly stratifies TNBC patients into slow cycling (low KAMS) cyclophosphamide-methotrexate-fluorouracil (CMF)-responsive and fast cycling (high KAMS) CMF-resistant subgroups. In this study, we reviewed clinical data from 124 CMF-treated TNBC patients from Nottingham Hospital and sought correlations between cycling kinetics (High/Low KAMS) and tumor infiltrating immune cells. Results: We found that slow cycling TNBCs had higher mean expression of tumor infiltrating immune cells than fast cycling TNBCs. Intratumoral CD68 (p = 0.003), CD3 (p = 0.006), CD20 (p = 0.01), FOXP3 (p = 0.01), and total numbers of intratumoral and stromal CD68 (p = 0.01) and CD3 (p = 0.03) expressing cells were found to be significantly higher in low KAMS tumors than in high KAMS tumors. Of these biomarkers, CD68 was significantly associated with patients’ breast cancer-specific survival (BCSS): (a) low KAMS, high CD68 TNBCs had better BCSS than low KAMS, low CD68 (p = 0.01) TNBCs, and (b) high KAMS, low CD68 cases had better BCSS than high KAMS, high CD68 cases. Conclusions: Our observation that there are more TILs in slow cycling TNBCs suggests that there may be a dynamic cross-regulation between cycling kinetics and antitumor immune response. From our surprising observation that CD68 exerts polar roles in low/high KAMS subgroups, we propose that distinctions in M1 and M2 macrophage subsets in slow and fast cycling TNBCs may correlate with distinct outcomes. In addition, metabolic competition between tumor and immune cells may determine the level and function of TILs.

Prognostic value of vitamin D receptor and insulin-like growth factor receptor 1 expression in triple-negative breast cancer

2017 ◽  
Vol 71 (1) ◽  
pp. 34-39 ◽  
Author(s):  
Martina Soljic ◽  
Ivana Mrklic ◽  
Snjezana Tomic ◽  
Tomislav Omrcen ◽  
Nikica Sutalo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Vitamin D ◽  
Overall Survival ◽  
Growth Factor ◽  
Vitamin D Receptor ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Growth Factor Receptor ◽  
Insulin Like Growth Factor ◽  
Ki 67

AimTriple-negative breast cancer (TNBC) is characterised by shorter overall survival and an early peak of distant recurrences with still no specific targeted treatment available. Vitamin D receptor (VDR) and insulin-like growth factor receptor 1 (IGFR) have recently been described as potential new targets for anticancer therapy, yet their roles in TNBCs are still to be explored. In this study we investigated VDR and IGFR expression in patients with TNBC and compared them with clinical and pathological parameters and survival to possibly demonstrate their prognostic and therapeutic relevance.MethodsThe study included 96 patients with TNBC. Clinical and pathological parameters were compared with the immunohistochemical expression of VDR and IGFR.ResultsPositive VDR immunostaining was present in 27% of tumours and inversely correlated with higher mitotic score, histological grade and higher proliferation index measured by Ki-67 and related to the increased overall survival (OS). Out of 96 patients with TNBC, 35.5% of tumours were IGFR positive and correlated with higher mitotic score and Ki-67, and strongly correlated with shorter disease-free survival (DFS). Patients with VDR-negative and IGF-positive tumours had significantly lower DFS and OS.ConclusionApproximately one third of TNBCs express VDR and/or IGFR. Their expression is linked with the recurrence of the disease and survival, which make them possible targets for treatment and a prognostic tool for dividing TNBCs into more homogeneous subgroups.

scholarly journals Tumor microenvironment in triple-negative breast cancer: the correlation of tumor-associated macrophages and tumor-infiltrating lymphocytes

2021 ◽  
Author(s):  
H. Kuroda ◽  
T. Jamiyan ◽  
R. Yamaguchi ◽  
A. Kakumoto ◽  
A. Abe ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cytotoxic T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Tumor Associated Macrophages ◽  
Free Survival ◽  
Infiltrating Lymphocytes

Abstract Purpose Immune cells such as cytotoxic T cells, helper T cells, B cells or tumor-associated macrophages (TAMs) contribute to the anti-tumor response or pro-tumorigenic effect in triple negative breast cancer (TNBC). The interrelation of TAMs, T and B tumor-infiltrating lymphocytes (TILs) in TNBC has not been fully elucidated. Methods We evaluated the association of tumor-associated macrophages, T and B TILs in TNBC. Results TNBCs with a high CD68+, CD163+ TAMs and low CD4+, CD8+, CD20+ TILs had a significantly shorter relapse-free survival (RFS) and overall survival (OS) than those with low CD68+, CD163+ TAMs and high CD4+, CD8+, CD20+ TILs. TNBCs with high CD68+ TAMs/low CD8+ TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD68+ TAMs/high CD8+ TILs, low CD68+ TAMs/high CD8+ TILs, and low CD68+/low CD8+. TNBCs with high CD163+ TAMs/low CD8+, low CD20 + TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD163+ TAMs/high CD8+ TILs and high CD163+ TAMs /high CD20+ TILs. Conclusions Our study suggests that TAMs further create an optimal tumor microenvironment (TME) for growth and invasion of cancer cells when evasion of immunoreactions due to T and B TILs occurs. In TNBCs, all these events combine to affect prognosis. The process of TME is highly complex in TNBCs and for an improved understanding, larger validation studies are necessary to confirm these findings.

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 Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer

2017 ◽  
Vol 173 ◽  
pp. 122-129 ◽  
Author(s):  
Naing Lin Shan ◽  
Joseph Wahler ◽  
Hong Jin Lee ◽  
Min Ji Bak ◽  
Soumyasri Das Gupta ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Vitamin D ◽  
Triple Negative Breast Cancer ◽  
Triple Negative
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