Loss of the proprotein convertase Furin in T cells represses mammary tumorigenesis in oncogene-driven triple negative breast cancer

2020 ◽  
Vol 484 ◽  
pp. 40-49 ◽  
Author(s):  
Zongsheng He ◽  
Abdel-Majid Khatib ◽  
John W.M. Creemers
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Mammary Tumorigenesis ◽  
Proprotein Convertase

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.

Regulatory T cells: Their role in triple‐negative breast cancer progression and metastasis

Cancer ◽  
2022 ◽  
Author(s):  
Rama Rao Malla ◽  
Padmaraju Vasudevaraju ◽  
Rahul Kumar Vempati ◽  
Marni Rakshmitha ◽  
Neha Merchant ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Progression

scholarly journals An innate-like Vδ1+ γδ T cell compartment in the human breast is associated with remission in triple-negative breast cancer

2019 ◽  
Vol 11 (513) ◽  
pp. eaax9364 ◽  
Author(s):  
Yin Wu ◽  
Fernanda Kyle-Cezar ◽  
Richard T. Woolf ◽  
Cristina Naceur-Lombardelli ◽  
Julie Owen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Human Breast ◽  
Cell Compartment ◽  
Αβ T Cells

Innate-like tissue-resident γδ T cell compartments capable of protecting against carcinogenesis are well established in mice. Conversely, the degree to which they exist in humans, their potential properties, and their contributions to host benefit are mostly unresolved. Here, we demonstrate that healthy human breast harbors a distinct γδ T cell compartment, primarily expressing T cell receptor (TCR) Vδ1 chains, by comparison to Vδ2 chains that predominate in peripheral blood. Breast-resident Vδ1+ cells were functionally skewed toward cytolysis and IFN-γ production, but not IL-17, which has been linked with inflammatory pathologies. Breast-resident Vδ1+ cells could be activated innately via the NKG2D receptor, whereas neighboring CD8+ αβ T cells required TCR signaling. A comparable population of Vδ1+ cells was found in human breast tumors, and when paired tumor and nonmalignant samples from 11 patients with triple-negative breast cancer were analyzed, progression-free and overall survival correlated with Vδ1+ cell representation, but not with either total γδ T cells or Vδ2+ T cells. As expected, progression-free survival also correlated with αβ TCRs. However, whereas in most cases TCRαβ repertoires focused, typical of antigen-specific responses, this was not observed for Vδ1+ cells, consistent with their innate-like responsiveness. Thus, maximal patient benefit may accrue from the collaboration of innate-like responses mounted by tissue-resident Vδ1+ compartments and adaptive responses mounted by αβ T cells.

Abstract 465: Progestin-driven regulatory T cells directly promote an aggressive and metastatic phenotype in triple-negative breast cancer

2015 ◽  
Author(s):  
Tomas Dalotto Moreno ◽  
Juan Pablo Cerliani ◽  
Diego Omar Croci ◽  
Santiago Patricio Mendez-Huergo ◽  
Florencia Moses ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Metastatic Phenotype

Abstract 2305: Tumor MUC1 glycoprotein-highly specific CAR T cells control triple-negative breast cancer

2019 ◽  
Author(s):  
Ru Zhou ◽  
Mahboubeh Yazdanifar ◽  
Lopamudra Das Roy ◽  
John Maher ◽  
Pinku Mukherjee
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Car T Cells ◽  
Car T ◽  
Muc1 Glycoprotein

scholarly journals Nomogram Personalizes and Visualizes the Overall Survival of Patients with Triple-Negative Breast Cancer Based on the Immune Genome

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Peipei Wang ◽  
Yang Fu ◽  
Yueyun Chen ◽  
Qing Li ◽  
Ye Hong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
T Cells ◽  
Risk Score ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Novel Therapy ◽  
Immune Biomarkers ◽  
Poorly Differentiated ◽  
Immune Related Genes

Background. Triple-negative breast cancer (TNBC) is usually poorly differentiated, highly invasive, susceptible to distant metastasis, and less responsive to endocrine and targeted therapy. However, immunotherapy is a promising treatment for TNBC patients recently. Methods. The prognostic value of immune-related genes (IRGs) was explored by using RNA sequencing and microarray data of 123 and 107 TNBC patients from TCGA and GEO databases, respectively. Results. In TCGA database, GO and KEGG pathway analysis of 119 differential IRGs indicated that they actively participate in the interaction of cytokines and receptors. A nomogram model constructed by the prognosis-related CCL25, IL29, TDGF3, GPR44, and GREM2 in the IRGs could personalize and visualize the 1-, 2-, 3-, 4-, and 5-year overall survival (OS) of TNBC patients. Moreover, TNBC patients could be defined as low-risk ( risk   score < 194 ) or high-risk ( risk   score ≥ 194 ) cohorts based on the risk score derived from the nomogram model. The results could be validated by the GSE58812 dataset. Furthermore, the risk score was an independent risk factor for TNBC patients ( HR = 1.019 , 95% CI 1.012-1.027, p < 0.001 ) and was positively related to stage ( p = 0.017 ). Interestingly, the risk score could reflect the infiltration of B cells, CD4+ T cells, CD8+ T cells, dendritic cells, and neutrophils. Conclusion. These findings provided a reference for personalized OS prediction in TNBC patients and might be potential immune biomarkers for designing novel therapy.

Phase I trial of autologous cMET-directed CAR-t cells administered intravenously in patients with melanoma & breast carcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10035-10035
Author(s):  
Payal D Shah ◽  
Alexander Chan Chi Huang ◽  
Xiaowei Xu ◽  
Paul J. Zhang ◽  
Robert Orlowski ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
Phase I ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Car T Cells ◽  
Car T ◽  
Post Infusion ◽  
Infusion Period

10035 Background: Advanced relapsed/refractory melanoma and metastatic triple-negative breast cancer are lethal diseases for which effective therapies are limited. We conducted a pilot phase I clinical trial (NCT03060356) to establish the safety and feasibility of intravenous autologous chimeric antigen receptor (CAR) T cell immunotherapy targeting cMET, a cell-surface antigen that is highly expressed in these cancers. Methods: Subjects had metastatic or unresectable melanoma (Mel) or triple-negative breast cancer (BC) with ≥30% expression of cMET on archival tissue or screening biopsy. Eligible subjects had measurable disease and progression on at least 1 prior therapy. Patients (pts) received up to 6 doses (1x108 total T-cells per dose) of RNA electroporated anti-cMET CAR T cells over a 2-week period without antecedent lymphodepleting chemotherapy. Subjects underwent pre- and post-infusion biopsies. The primary objective was to determine feasibility and safety of treatment. Results: 77 subjects (39 mel, 38 BC) were prescreened for tumor cMET expression and 37 (17 mel, 20 BC) met the eligibility threshold. Seven pts (4 BC, 3 Mel) received cMET-directed CAR T infusions on study. Mean age was 50 years (35-64); median (M) ECOG 0 (0-1); M prior lines of chemotherapy/immunotherapy were 4/0 for BC pts and 1/3 for Mel pts. 6 of 7 pts received all planned CAR T cell infusions, and 1 received 5 infusions. 5 pts experienced grade (G) 1 or G 2 toxicity that was possibly or definitely related to study. Toxicities occurring in ≥1 pt included: anemia (n = 3), fatigue (n = 2), and malaise (n = 2). No G ≥3 toxicities or cytokine release syndrome were observed. No pts discontinued therapy due to toxicity. Best response was stable disease in 4 pts (2 BC, 2 Mel) and PD in 3 pts (2 BC, 1 Mel). Messenger RNA signals corresponding to CAR T cells were detected by RT-PCR in the peripheral blood of all pts during the infusion period and in 2 pts after the infusion period. 6 pts underwent baseline biopsy and 4 pts underwent post-infusion biopsy. Immunohistochemical stains of CD3, CD4, CD8, CD163, L26, PD1, PDL1, Foxp3, Ki67, Granzyme B and Phospho-S6 were performed on pre- and post-treatment tissue biopsies and are being evaluated. Conclusions: Intravenous administration of RNA-electroporated cMET-directed CAR T cells was safe and feasible. Future directions include examination of this target using a lentiviral construct in combination with lymphodepleting chemotherapy. Clinical trial information: NCT03060356.

WNT/β–catenin pathway activation correlates with the increase of tumor-associated macrophages in triple negative breast cancer (TNBC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12564-e12564
Author(s):  
Eleonora Timperi ◽  
Mengliang Ye ◽  
Thierry Dubois ◽  
Didier Meseure ◽  
Anne Vincent- Salomon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Early Stage ◽  
Immune Checkpoint Blockade ◽  
Tumor Associated Macrophages ◽  
T Cell Exclusion

e12564 Background: Triple negative breast cancer (TNBC) occurs in about 20% of all breast carcinomas. Because only a fraction of TNBCs responding to immune checkpoint blockade show a pre-existing T cell-inflamed tumor microenvironment (TME), it is critical to understand the mechanisms of T-cell exclusion. Tumor-cell intrinsic activation of the WNT/β–catenin pathway, overexpressed in 30% of human breast cancers, is linked to a T-cell excluded TME. In β–cateninhigh TNBC, however, the quality of the myeloid compartment has not been evaluated. Methods: A total of seventy-five, early-stage, untreated, TNBC patients was assessed (patient cohorts approved by IRB). β–catenin expression was detected by IHC and scored as high, intermediate, and low. The presence of T cells, tumor-associated macrophages (TAMs) and LAMP-expressing dendritic cells (LAMP+ DCs) was assessed by IHC using aCD3, aCD68, aCD163, and aLAMP, respectively. Public TNBC datasets TCGA (N = 157) and METABRIC (N = 319) were interrogated for correlations between β–catenin- and immune-associated genes. Results: Three patient groups (N = 25/group) were identified according to the negative, medium and high intracellular expression of β–catenin. As opposed to β–cateninlow TNBC, the β–cateninhigh group displayed significantly lower CD3+ T cells (median 5% ±7.37 SD vs median 30% ± 18.28 SD, p < 0.0001) and LAMP+ DCs (median 1% ± 2.515 SD vs median 10% ± 7.038 SD, p < 0.0001). The β–cateninlow group was enriched in lymphocyte-predominant TNBC. For the first time, we show that the immune-suppressive, CD68+CD163+ TAMs were strongly accumulated in the β–cateninhigh group (median 20% ± 12.20 SD vs median 5% ± 6.831 SD, p < 0.0001). The interrogation of the public TNBC datasets TCGA and METABRIC confirmed that – after patient statification according to the expression level of a WNT/β–catenin gene-signature (i.e. MMP7, SFRP1, WNT10A, WNT16, WNT9B) – multiple TAM-associated genes – identified by our group in a single-cell RNAseq dataset – were strongly upregulated in WNT/β–cateninhigh signature, highlighting the role of the WNT/β–catenin signaling pathway not only in T-cell exclusion but also in selective TAM accumulation. Conclusions: Immune-suppressive TAMs are accumulated in β–cateninhigh, T-cell excluded TNBCs emphasizing the importance of tumor-intrinsic factors in shaping the quality of the immune infiltrate.

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