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1.
J Exp Clin Cancer Res ; 41(1): 132, 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35392977

RESUMO

BACKGROUND: Interactions between tumor and microenvironment determine individual response to immunotherapy. Triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) have exhibited suboptimal responses to immune checkpoint inhibitors (ICIs). Aspartate ß-hydroxylase (ASPH), an oncofetal protein and tumor associated antigen (TAA), is a potential target for immunotherapy. METHODS: Subcutaneous HCC and orthotopic TNBC murine models were established in immunocompetent BALB/c mice with injection of BNL-T3 and 4 T1 cells, respectively. Immunohistochemistry, immunofluorescence, H&E, flow cytometry, ELISA and in vitro cytotoxicity assays were performed. RESULTS: The ASPH-MYC signaling cascade upregulates PD-L1 expression on breast and liver tumor cells. A bio-nanoparticle based λ phage vaccine targeting ASPH was administrated to mice harboring syngeneic HCC or TNBC tumors, either alone or in combination with PD-1 blockade. In control, autocrine chemokine ligand 13 (CXCL13)-C-X-C chemokine receptor type 5 (CXCR5) axis promoted tumor development and progression in HCC and TNBC. Interactions between PD-L1+ cancer cells and PD-1+ T cells resulted in T cell exhaustion and apoptosis, causing immune evasion of cancer cells. In contrast, combination therapy (Vaccine+PD-1 inhibitor) significantly suppressed primary hepatic or mammary tumor growth (with distant pulmonary metastases in TNBC). Adaptive immune responses were attributed to expansion of activated CD4+ T helper type 1 (Th1)/CD8+ cytotoxic T cells (CTLs) that displayed enhanced effector functions, and maturation of plasma cells that secreted high titers of ASPH-specific antibody. Combination therapy significantly reduced tumor infiltration of immunosuppressive CD4+/CD25+/FOXP3+ Tregs. When the PD-1/PD-L1 signal was inhibited, CXCL13 produced by ASPH+ cancer cells recruited CXCR5+/CD8+ T lymphocytes to tertiary lymphoid structures (TLSs), comprising effector and memory CTLs, T follicular helper cells, B cell germinal center, and follicular dendritic cells. TLSs facilitate activation and maturation of DCs and actively recruit immune subsets to tumor microenvironment. These CTLs secreted CXCL13 to recruit more CXCR5+ immune cells and to lyse CXCR5+ cancer cells. Upon combination treatment, formation of TLSs predicts sensitivity to ICI blockade. Combination therapy substantially prolonged overall survival of mice with HCC or TNBC. CONCLUSIONS: Synergistic antitumor efficacy attributable to a λ phage vaccine specifically targeting ASPH, an ideal TAA, combined with ICIs, inhibits tumor growth and progression of TNBC and HCC.


Assuntos
Vacinas Anticâncer , Carcinoma Hepatocelular , Imunoterapia , Neoplasias Hepáticas , Neoplasias de Mama Triplo Negativas , Animais , Antígeno B7-H1 , Vacinas Anticâncer/imunologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/terapia , Humanos , Inibidores de Checkpoint Imunológico , Imunidade , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Camundongos , Nanopartículas , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/terapia , Microambiente Tumoral
2.
Breast Cancer Res Treat ; 193(1): 83-94, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35194731

RESUMO

PURPOSE: To investigate real-world clinical outcomes in patients with BRCA-mutated (BRCAm), HER2-negative metastatic breast cancer (mBC) according to BRCA and hormone receptor (HR) status. METHODS: Patients diagnosed with HER2-negative mBC between 01 January 2010 and 31 December 2018 were retrospectively identified from the American Society of Clinical Oncology's CancerLinQ Discovery® database. Time to first subsequent therapy or death (TFST) from date of mBC diagnosis and start of first-line treatment for mBC and overall survival (OS) from date of mBC diagnosis were investigated according to BRCA status (BRCAm, BRCA wild type [BRCAwt] or unknown BRCA [BRCAu]) and HR status (positive/triple negative breast cancer [TNBC]). Follow-up continued until 31 August 2019 (i.e. minimum of 8 months). RESULTS: 3744 patients with HER2-negative mBC were identified (BRCAwt, n = 460; BRCAm, n = 83; BRCAu, n = 3201) (HR-positive, n = 2738). Median (Q1, Q3) age was 63.0 (54.0, 73.0) years. Median (95% confidence interval [CI]) TFST (months) from mBC diagnosis was as follows: HR-positive, 7.7 (5.0, 11.2), 8.3 (6.6, 10.2) and 9.4 (8.7, 10.1); TNBC, 5.4 (3.9, 12.4), 5.6 (4.7, 6.6) and 5.4 (5.0, 6.2) for BRCAm, BRCAwt and BRCAu, respectively. Median (95% CI) OS (months) was as follows: HR-positive, 41.1 (31.5, not calculable), 55.1 (43.5, 65.5) and 33.0 (31.3, 34.8); TNBC, 13.7 (11.1, not calculable), 14.4 (10.7, 17.0) and 11.7 (10.3, 12.8) for BRCAm, BRCAwt and BRCAu, respectively. CONCLUSION: When stratified by HR status, TFST and OS were broadly similar for patients with HER2-negative mBC, irrespective of BRCA status. Further global real-world studies are needed to study outcomes of this patient population.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/terapia , Feminino , Humanos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/terapia
3.
J Control Release ; 343: 303-313, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35104570

RESUMO

Interactions between different cell types in the tumor microenvironment (TME) affect tumor growth. Tumor-associated fibroblasts produce C-X-C motif chemokine ligand 13 (CXCL13) which recruits B cells to the TME. B-cells in the TME differentiate into regulatory B cells (Bregs) (IL-10+CD1d+CD5+CD138+CD19+). We highlight these Breg cells as a new important factor in the modulation of the immunosuppressive TME in different desmoplastic murine tumor models. In addition, CXCL13 also stimulates epithelial-mesenchymal transition (EMT) of the tumor cells. The tumorigenic roles of CXCL13 led us to explore an innovative anti-cancer strategy based on delivering plasmid DNA encoding a CXCL13 trap to reduce Bregs differentiation and normalize EMT, thereby suppressing tumor growth. CXCL13 trap suppressed tumor growth in pancreatic cancer, BRAF-mutant melanoma, and triple-negative breast cancer. In this study, following treatment, the affected tumor remained dormant resulting in prolonged progression-free survival of the host.


Assuntos
Linfócitos B Reguladores , Fibroblastos Associados a Câncer , Neoplasias Pancreáticas , Neoplasias de Mama Triplo Negativas , Animais , Linfócitos B Reguladores/metabolismo , Quimiocina CXCL13/genética , Quimiocina CXCL13/metabolismo , Humanos , Camundongos , Neoplasias Pancreáticas/metabolismo , Neoplasias de Mama Triplo Negativas/terapia , Microambiente Tumoral
4.
Crit Rev Oncol Hematol ; 172: 103643, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35217131

RESUMO

Triple-negative breast cancers (TNBC) comprise biologically and clinically heterogeneous diseases characterized by the lack of hormone receptors (HR) and HER2 expression. This subset of tumors accounts for 15-20% of all breast cancers and pursues an ominous clinical course. However, there is a spectrum of low-risk TNBCs with no/minimal metastatic potential, including the salivary gland-type tumors, those with extensive apocrine differentiation and/or high tumor-infiltrating lymphocytes, and small-sized, early-stage (pT1a/bN0M0) TNBCs. De-escalating the treatment in low-risk TNBC, however, is not trivial because of the substantial lack of dedicated randomized clinical trials and cancer registries. The development of new diagnostic and/or prognostic biomarkers based on clinical and molecular aspects of low-risk TNBCs would lead to improved clinical treatment. Here, we sought to provide a portrait of the clinicopathological and molecular features of low-risk TNBC, with a focus on the diagnostic challenges along with the most important biological characteristics underpinning their favorable clinical course.


Assuntos
Neoplasias de Mama Triplo Negativas , Biomarcadores Tumorais , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Prognóstico , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/terapia
5.
Clin Transl Med ; 12(1): e724, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35090088

RESUMO

Due to the heterogeneity and high frequency of genome mutations in cancer cells, targeting vital protumour factors found in stromal cells in the tumour microenvironment may represent an ideal strategy in cancer therapy. However, the regulation and mechanisms of potential targetable therapeutic candidates need to be investigated. An in vivo study demonstrated that loss of pentraxin 3 (PTX3) in stromal cells significantly decreased the metastasis and growth of cancer cells. Clinically, our results indicate that stromal PTX3 expression correlates with adverse prognostic features and is associated with worse survival outcomes in triple-negative breast cancer (TNBC). We also found that transforming growth factor beta 1 (TGF-ß1) induces PTX3 expression by activating the transcription factor CCAAT/enhancer binding protein delta (CEBPD) in stromal fibroblasts. Following PTX3 stimulation, CD44, a PTX3 receptor, activates the downstream ERK1/2, AKT and NF-κB pathways to specifically contribute to the metastasis/invasion and stemness of TNBC MDA-MB-231 cells. Two types of PTX3 inhibitors were developed to disrupt the PTX3/CD44 interaction and they showed a significant effect on attenuating growth and restricting the metastasis/invasion of MDA-MB-231 cells, suggesting that targeting the PTX3/CD44 interaction could be a new strategy for future TNBC therapies.


Assuntos
Proteína C-Reativa/efeitos dos fármacos , Receptores de Hialuronatos/efeitos dos fármacos , Componente Amiloide P Sérico/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética , Proteína C-Reativa/genética , Feminino , Humanos , Receptores de Hialuronatos/genética , Componente Amiloide P Sérico/genética , Neoplasias de Mama Triplo Negativas/terapia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
6.
Sci Rep ; 12(1): 1470, 2022 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-35087134

RESUMO

Triple negative breast cancer (TNBC) is characterized by clinical aggressiveness, lack of recognized target therapy, and a dismal patient prognosis. Several studies addressed genomic changes occurring during neoadjuvant chemotherapy (NAC) focusing on somatic variants, but without including copy number alterations (CNAs). We analyzed CNA profiles of 31 TNBC primary tumor samples before and after NAC and of 35 single circulating tumor cells (CTCs) collected prior, during and after treatment by using next-generation sequencing targeted profile and low-pass whole genome sequencing, respectively. In pre-treatment tissue samples, the most common gains occurred on chromosomes 1, 2 and 8, and SOX11 and MYC resulted the most altered genes. Notably, amplification of MSH2 (4/4 versus 0/12, p < 0.01) and PRDM1 and deletion of PAX3 (4/4 versus 1/12, p < 0.01) significantly characterized primary tumors of patients with pathological complete response. All patients with paired pre- and post-NAC samples reported a change in post-treatment CNAs compared to baseline, despite they showed at least one common alteration. CNAs detected after treatment involved genes within druggable pathways such as EGFR, cell cycle process and Ras signaling. In two patients, CTCs shared more alterations with residual rather than primary tumor involving genes such as MYC, BCL6, SOX2, FGFR4. The phylogenetic analysis of CTCs within a single patient revealed NAC impact on tumor evolution, suggesting a selection of driver events under treatment pressure. In conclusion, our data showed how chemoresistance might arise early from treatment-induced selection of clones already present in the primary tumor, and that the characterization of CNAs on single CTCs informs on cancer evolution and potential druggable targets.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Variações do Número de Cópias de DNA/efeitos dos fármacos , Terapia Neoadjuvante , Células Neoplásicas Circulantes/patologia , Neoplasias de Mama Triplo Negativas/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Mama/patologia , Mama/cirurgia , Estudos de Coortes , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Mastectomia , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Filogenia , Prognóstico , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Sequenciamento Completo do Genoma
7.
Annu Rev Pathol ; 17: 181-204, 2022 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-35073169

RESUMO

Triple-negative breast cancer (TNBC) encompasses a heterogeneous group of fundamentally different diseases with different histologic, genomic, and immunologic profiles, which are aggregated under this term because of their lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. Massively parallel sequencing and other omics technologies have demonstrated the level of heterogeneity in TNBCs and shed light into the pathogenesis of this therapeutically challenging entity in breast cancer. In this review, we discuss the histologic and molecular classifications of TNBC, the genomic alterations these different tumor types harbor, and the potential impact of these alterations on the pathogenesis of these tumors. We also explore the role of the tumor microenvironment in the biology of TNBCs and its potential impact on therapeutic response. Dissecting the biology and understanding the therapeutic dependencies of each TNBC subtype will be essential to delivering on the promise of precision medicine for patients with triple-negative disease.


Assuntos
Neoplasias de Mama Triplo Negativas , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/uso terapêutico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/terapia , Microambiente Tumoral/genética
8.
Biomaterials ; 281: 121371, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35063740

RESUMO

Discovery of effective chemical sensitizers to synergize with natural killer cells immunotherapy is urgently desired to overcome its unsatisfactory efficacy in clinic. Herein, we design a series of ruthenium (Ru) polypyridyl complex to systematically explore their potentials in facilitating NK cells treatment. Intriguingly, the chemical structure greatly determines the activity of Ru complexes, while only RuPOP effectively regulates the immuno-suppressors and target proteins within tumor cells. This unique property contributes to its good capability in enhancing the sensitivity of MDA-MB-231 cells to NK cells from cancer patients. Furthermore, besides directly damaging tumor cells, RuPOP pretreatment together with NK cells can also induce robust ROS generation, activate multiple apoptosis-related receptors like TNF-R1, DR5, Fas and maximize the interactions between NK and tumor cells via up-regulating NKG2D and its multiple ligands to trigger caspase 3-dependent apoptosis. Moreover, the combination treatment exhibits high in vivo therapeutic efficacy against breast tumor through boosting the infiltration of NK cells and reducing the protumoral capability of myeloid-derived suppressor cells (MDSC). This study sheds lights for designing metal complexes to potentiate NK cells immunotherapy with clear action mechanisms and provides important information for developing more effective adoptive cell transfer therapy in clinic.


Assuntos
Rutênio , Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Humanos , Imunoterapia , Imunoterapia Adotiva , Células Matadoras Naturais , Rutênio/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/terapia
9.
BMC Cancer ; 22(1): 41, 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34991520

RESUMO

BACKGROUND: Nowadays, evaluation of the efficacy and the duration of treatment, in context of monitoring patients with solid tumors, is based on the RECIST methodology. With these criteria, resistance and/or insensitivity are defined as tumor non-response which does not allow a good understanding of the diversity of the underlying mechanisms. The main objective of the OncoSNIPE® collaborative clinical research program is to identify early and late markers of resistance to treatment. METHODS: Multicentric, interventional study with the primary objective to identify early and / or late markers of resistance to treatment, in 600 adult patients with locally advanced or metastatic triple negative or Luminal B breast cancer, non-small-cell lung cancer or pancreatic ductal adenocarcinoma. Patients targeted in this study have all rapid progression of their pathology, making it possible to obtain models for evaluating markers of early and / or late responses over the 2-year period of follow-up, and thus provide the information necessary to understand resistance mechanisms. To explore the phenomena of resistance, during therapeutic response and / or progression of the pathology, we will use a multidisciplinary approach including high-throughput sequencing (Exome-seq and RNAseq), clinical data, medical images and immunological profile by ELISA. Patients will have long-term follow-up with different biological samples, at baseline (blood and biopsy) and at each tumoral evaluation or tumoral progression evaluated by medical imaging. Clinical data will be collected through a dedicated Case Report Form (CRF) and enriched by semantic extraction based on the French ConSoRe (Continuum Soins Recherche) initiative, a dedicated Semantic Clinical Data Warehouse (SCDW) to cancer. The study is sponsored by Oncodesign (Dijon, France) and is currently ongoing. DISCUSSION: The great diversity of intrinsic or acquired molecular mechanisms involved in resistance to treatment constitutes a real therapeutic issue. Improving understanding of mechanisms of resistance of cancer cells to anti-tumor treatments is therefore a major challenge. The OncoSNIPE cohort will lead to a better understanding of the mechanisms of resistance and will allow to explore new mechanisms of actions and to discover new therapeutic targets or strategies making it possible to circumvent the escape in different types of cancer. TRIAL REGISTRATION: Clinicaltrial.gov. Registered 16 September 2020, https://clinicaltrials.gov/ct2/show/NCT04548960?term=oncosnipe&draw=2&rank=1 and ANSM ID RCB 2017-A02018-45.


Assuntos
Neoplasias/terapia , Critérios de Avaliação de Resposta em Tumores Sólidos , Adulto , Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Resistência à Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Neoplasias/patologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapia
10.
Sci Rep ; 12(1): 729, 2022 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-35031634

RESUMO

Individuals diagnosed with metastatic triple-negative breast cancer (mTNBC) suffer worse survival rates than their metastatic non-TNBC counterparts. There is little information on survival, treatment patterns, and medical costs of mTNBC patients in Asia. Therefore, this study aimed to examine 5-year survival, regimens of first-line systemic therapy, and healthcare costs of mTNBC patients in Taiwan. Adult females newly diagnosed with TNBC and non-TNBC as well as their survival data, treatment regimens and costs of health services were identified and retrieved from the Cancer Registry database, Death Registry database, and National Health Insurance (NHI) claims database. A total of 9691 (19.27%) women were identified as TNBC among overall BC. The 5-year overall survival rate of TNBC and non-TNBC was 81.28% and 86.50%, respectively, and that of mTNBC and metastatic non-TNBC was 10.81% and 33.46%, respectively. The majority of mTNBC patients received combination therapy as their first-line treatment (78.14%). The 5-year total cost in patients with metastatic non-TNBC and with mTNBC was NTD1,808,693 and NTD803,445, respectively. Higher CCI scores were associated with an increased risk of death and lower probability of receiving combination chemotherapy. Older age was associated with lower 5-year medical costs. In sum, mTNBC patients suffered from poorer survival and incurred lower medical costs than their metastatic non-TNBC counterparts. Future research will be needed when there are more treatment options available for mTNBC patients.


Assuntos
Custos de Cuidados de Saúde , Neoplasias de Mama Triplo Negativas/economia , Neoplasias de Mama Triplo Negativas/terapia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bases de Dados Factuais , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Taxa de Sobrevida , Taiwan/epidemiologia , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Adulto Jovem
11.
Breast Cancer Res Treat ; 191(2): 243-255, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34716870

RESUMO

Immunotherapy has resulted in unprecedented gains in long-term outcomes for many cancer types and has revolutionized the treatment landscape of solid tumor oncology. Checkpoint inhibition in combination with chemotherapy has proven to be effective for the treatment of a subset of advanced triple-negative breast cancer in the first-line setting. This initial success is likely just the tip of the iceberg as there is much that remains unknown about how to best harness the immune system as a therapeutic strategy in all breast cancer subtypes. Therefore, numerous ongoing studies are currently underway to evaluate the safety and efficacy of immunotherapy in breast cancer. In this review, we will discuss emerging immunotherapeutic strategies for breast cancer treatment including the following: (1) Intratumoral therapies, (2) Anti-tumor vaccines, (3) B-specific T-cell engagers, and (4) Chimeric antigen receptor T-cell therapy, and (5) Emerging systemic immunotherapy strategies. For each topic, we will review the existing preclinical and clinical literature, discuss ongoing clinical trials, and highlight future directions in the field.


Assuntos
Neoplasias da Mama , Vacinas Anticâncer , Neoplasias de Mama Triplo Negativas , Neoplasias da Mama/terapia , Terapia Combinada , Feminino , Humanos , Imunoterapia , Neoplasias de Mama Triplo Negativas/terapia
12.
Breast Cancer Res Treat ; 191(2): 229-241, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34714450

RESUMO

PURPOSE: Immune checkpoint inhibition (ICI) has demonstrated clinically significant efficacy when combined with chemotherapy in triple negative breast cancer (TNBC). Although many patients derived benefit, others do not respond to immunotherapy, therefore relying upon innovative combinations to enhance response. Local therapies such as radiation therapy (RT) and cryotherapy are immunogenic and potentially optimize responses to immunotherapy. Strategies combining these therapies and ICI are actively under investigation. This review will describe the rationale for combining ICI with targeted local therapies in breast cancer. METHODS: A literature search was performed to identify pre-clinical and clinical studies assessing ICI combined with RT or cryotherapy published as of August 2021 using PubMed and ClinicalTrials.gov. RESULTS: Published studies of ICI with RT and IPI have demonstrated safety and signals of early efficacy. CONCLUSION: RT and cryotherapy are local therapies that can be integrated safely with ICI and has shown promise in early trials. Randomized phase II studies testing both of these approaches, such as P-RAD (NCT04443348) and ipilimumab/nivolumab/cryoablation for TNBC (NCT03546686) are current enrolling. The results of these studies are paramount as they will provide long term data on the safety and efficacy of these regimens.


Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias de Mama Triplo Negativas , Ensaios Clínicos Fase II como Assunto , Crioterapia , Humanos , Imunoterapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias de Mama Triplo Negativas/terapia
13.
Nat Rev Clin Oncol ; 19(2): 91-113, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34754128

RESUMO

Tumour heterogeneity and a long-standing paucity of effective therapies other than chemotherapy have contributed to triple-negative breast cancer (TNBC) being the subtype with the least favourable outcomes. In the past few years, advances in omics technologies have shed light on the relevance of the TNBC microenvironment heterogeneity, unveiling a close dynamic relationship with cancer cell features. An improved understanding of tumour-immune system co-evolution supports the need to adopt a more comprehensive view of TNBC as an ecosystem that encompasses the intrinsic and extrinsic features of cancer cells. This new appreciation of the biology of TNBC has already led to the development of novel targeted agents, including PARP inhibitors, antibody-drug conjugates and immune-checkpoint inhibitors, which are revolutionizing the therapeutic landscape and providing new opportunities both for patients with early-stage TNBC and for those with advanced-stage disease. The current therapeutic scenario is only the tip of the iceberg, as hundreds of new compounds and combinations are in development. The translation of these experimental therapies into clinical benefit is a welcome and ongoing challenge. In this Review, we describe the current and upcoming therapeutic landscape of TNBC and discuss how an integrated view of the TNBC ecosystem can define different levels of risk and provide improved opportunities for tailoring treatment.


Assuntos
Neoplasias de Mama Triplo Negativas/terapia , Feminino , Humanos , Neoplasias de Mama Triplo Negativas/patologia
14.
Cell Biol Int ; 46(2): 278-287, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34854515

RESUMO

T-cell-based immunotherapy and immune checkpoint blockade have been successfully used to treat several human solid cancers. The present study attempted to investigate the feasibility and efficacy of the antitumor effect of adoptive cell therapy along with programmed cell death protein 1 (PD-1) inhibitor on triple-negative breast cancer (TNBC). Tumor infiltration lymphocytes (TILs) from TNBC mouse tumor tissues were isolated and expanded, and TILs for adoptive cell therapy (TILs-ACT) were applied in combination with a PD-1 inhibitor to the TNBC mouse model. The pre- and post-therapy antitumor efficacy, cytokine secretion, and pathological changes were assessed both in vitro and in vivo. We found that TILs exhibited higher IFN-γ and TNF-α secretion than conventional T cells. The TILs-ACT combined with PD-1 inhibitor promoted active T-cell infiltration into the tumor tissue and exerted a strong antitumor effect in an in vivo model. Additionally, the strategy could downregulate the expression of inhibitory marker PD-1 on TILs. In conclusion, PD-1 blockade regulated T-cell exhaustion that synergized with adoptive TIL transfer immunotherapy, leading to eradication of established TNBC tumors. These findings might be useful in developing a feasible and effective therapeutic approach for TNBC.


Assuntos
Linfócitos do Interstício Tumoral , Neoplasias de Mama Triplo Negativas , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Humanos , Imunoterapia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Camundongos , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/uso terapêutico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/terapia
15.
Adv Ther ; 39(2): 943-958, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34918193

RESUMO

INTRODUCTION: Triple-negative breast cancer (TNBC) is associated with a high recurrence risk. However, the magnitude of direct and indirect costs associated with recurrence is lacking in the literature. METHODS: Adults 18-65 years old diagnosed with TNBC were identified from the OptumHealth Reporting and Insights claims database (1999-2017) and stratified by recurrence. For patients with recurrence, the index date was defined as 30 days before recurrence; for patients without recurrence, it was randomly assigned based on the distribution of time between first treatments and index dates of the recurrence cohort. All-cause and breast cancer-related healthcare resource utilization (HRU), direct and indirect costs, and work loss up to 1 year were compared between cohorts using generalized linear models. Kaplan-Meier analyses and Cox proportional hazards models compared the risk of leaving the workforce. RESULTS: Among the 2340 patients analyzed, mean age was 54 years and > 75% of patients had stage 0-2 cancer. Among the 1170 patients with recurrence, 236 were categorized as having metastatic recurrence and 934 as having locoregional recurrence. Relative to patients without recurrence, those with recurrence had significantly higher all-cause and breast cancer-related HRU. For instance, adjusted incidence rates (IRs) for all-cause inpatient admissions were 3.67 and 10.19 times higher for patients with locoregional and metastatic recurrence, respectively (p < 0.001). Adjusted all-cause healthcare costs were $8575/month higher for metastatic recurrence and $3609/month higher for locoregional recurrence vs. patients without recurrence (p < 0.001). Adjusted IRs for work loss days were approximately two times higher for locoregional and metastatic recurrence vs. without recurrence (p < 0.001). Patients with locoregional recurrence incurred $335/month more indirect costs vs. patients without recurrence; those with metastatic recurrence incurred $769/month more (p < 0.05). Patients with recurrence had a 63% higher rate of leaving the work force (p = 0.003). CONCLUSION: The incremental direct and indirect economic burden associated with recurrent TNBC is substantial relative to non-recurrence.


Assuntos
Neoplasias de Mama Triplo Negativas , Adolescente , Adulto , Idoso , Efeitos Psicossociais da Doença , Feminino , Estresse Financeiro , Custos de Cuidados de Saúde , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/terapia , Estados Unidos/epidemiologia , Adulto Jovem
16.
Mol Med Rep ; 25(2)2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34913063

RESUMO

CircRNAs are associated with adriamycin (ADM) resistance in triple­negative breast cancer (TNBC), but the mechanism is unknown. Reverse transcription­quantitative PCR was applied to quantify circular RNA (circRNA)_0044556, microRNA (miR)­145 and NRAS proto­oncogene, GTPase (NRAS) in TNBC tissues and cells with or without ADM treatment. Following ADM treatment, the effects of circRNA_0044556 on the viability, ADM resistance, apoptosis and migration of TNBC cells were investigated by cell function experiments (Cell Counting Kit­8, flow cytometry and Transwell assays). The targeting relationship between circRNA_0044556 and miR­145 was investigated via bioinformatics analysis, dual­luciferase reporter assay and RNA immunoprecipitation. The effects of the circRNA_0044556/miR­145 axis on the TNBC cells were revealed by rescue experiments. Correlations among circRNA_0044556, miR­145 and NRAS were analyzed by Pearson's correlation test. CircRNA_0044556 was highly expressed in TNBC tissues and cells with or without ADM­resistance. The overexpression of circRNA_0044556 promoted cell viability, ADM­resistance and migration, while inhibiting the apoptosis by sponging miR­145. Upregulation of miR­145 reversed the effects of circRNA_0044556 on the TNBC cells. CircRNA_0044556 was negatively correlated with miR­145 yet positively correlated with NRAS, the target gene of miR­145, in addition to the discovery suggesting the negative regulatory effects of circRNA_0044556 on miR­145. CircRNA_0044556 diminished the sensitivity of TNBC cells to ADM via the miR­145/NRAS axis.


Assuntos
Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , MicroRNAs/metabolismo , RNA Circular/metabolismo , Neoplasias de Mama Triplo Negativas/terapia , Adulto , Mama/patologia , Mama/cirurgia , Linhagem Celular Tumoral , Quimioterapia Adjuvante/métodos , Biologia Computacional , Doxorrubicina/uso terapêutico , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Mastectomia , Pessoa de Meia-Idade , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/cirurgia
17.
Cells ; 10(11)2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-34831064

RESUMO

Breast cancer remains a major cause of cancer-related deaths in women worldwide. Chemotherapy-promoted stemness and enhanced stem cell plasticity in breast cancer is a cause for great concern. The discovery of drugs targeting BCSCs was suggested to be an important advancement in the establishment of therapy that improves the efficacy of chemotherapy. In this work, by using single-cell mass cytometry, we observed that stemness in spheroid-forming cells derived from MDA-MB-231 cells was significantly increased after doxorubicin administration and up-regulated integrin αvß3 expression was also observed. An RGD-included nanoparticle (CS-V) was designed, and it was found that it could promote doxorubicin's efficacy against MDA-MB-231 spheroid cells. The above observations suggested that the combination of RGD-included nanoparticles (CS-V) with the chemo-drug doxorubicin could be developed as a potential therapy for breast cancer.


Assuntos
Nanopartículas/química , Proteômica , Análise de Célula Única , Neoplasias de Mama Triplo Negativas/terapia , Linhagem Celular Tumoral , Quitosana/química , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Feminino , Humanos , Integrina alfaVbeta3/metabolismo , Nanopartículas/ultraestrutura , Células-Tronco Neoplásicas/patologia , Tamanho da Partícula , Peptídeos/química , Esferoides Celulares/patologia
18.
Nature ; 599(7886): 673-678, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34732895

RESUMO

Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC)1. The extracellular matrix (ECM) contributes to immune exclusion2. However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes3,4. Here we show that discoidin domain receptor 1 (DDR1), a collagen receptor with tyrosine kinase activity5, instigates immune exclusion by promoting collagen fibre alignment. Ablation of Ddr1 in tumours promotes the intratumoral penetration of T cells and obliterates tumour growth in mouse models of TNBC. Supporting this finding, in human TNBC the expression of DDR1 negatively correlates with the intratumoral abundance of anti-tumour T cells. The DDR1 extracellular domain (DDR1-ECD), but not its intracellular kinase domain, is required for immune exclusion. Membrane-untethered DDR1-ECD is sufficient to rescue the growth of Ddr1-knockout tumours in immunocompetent hosts. Mechanistically, the binding of DDR1-ECD to collagen enforces aligned collagen fibres and obstructs immune infiltration. ECD-neutralizing antibodies disrupt collagen fibre alignment, mitigate immune exclusion and inhibit tumour growth in immunocompetent hosts. Together, our findings identify a mechanism for immune exclusion and suggest an immunotherapeutic target for increasing immune accessibility through reconfiguration of the tumour ECM.


Assuntos
Colágeno/metabolismo , Receptor com Domínio Discoidina 1/metabolismo , Matriz Extracelular/metabolismo , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Evasão Tumoral , Animais , Linhagem Celular Tumoral , Receptor com Domínio Discoidina 1/antagonistas & inibidores , Receptor com Domínio Discoidina 1/deficiência , Receptor com Domínio Discoidina 1/genética , Modelos Animais de Doenças , Matriz Extracelular/imunologia , Feminino , Deleção de Genes , Técnicas de Inativação de Genes , Humanos , Imunocompetência/imunologia , Imunoterapia , Camundongos , Linfócitos T/citologia , Linfócitos T/imunologia , Neoplasias de Mama Triplo Negativas/terapia
19.
Indian J Pathol Microbiol ; 64(4): 664-670, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34673583

RESUMO

BACKGROUND: The programmed cell death protein - 1 (PD-1) - programmed cell death ligand - 1 (PD-L1) axis is emerging as a promising target for immunotherapy in triple-negative breast cancers (TNBC). AIMS: We analyzed the expression of PD-L1 in TNBC cases, with special emphasis on lymphocyte-predominant tumors along with correlation of the same with clinicopathological features and outcome. SETTINGS AND DESIGN: Tissue microarrays (TMA) were prepared from resection specimens of TNBC cases diagnosed from 2004 to 2008. SUBJECTS AND METHODS: Immunohistochemical staining was performed on the TMA using the ventana PD-L1 antibody (Clone SP 263). STATISTICAL ANALYSIS: Chi-square test was used for correlation of PD-L1 positivity in tumor and immune cells with clinicopathological features. Univariate and multivariate survival analyses were carried out using the Kaplan Meir and Cox Regression methods, respectively. RESULTS: Overall, PD-L1 staining was seen in 35.9% (66 out of 184) tumors. PD-L1 positivity of tumor cells was seen in 14.7% (27 out of 184 cases), whereas stromal immune cell expression was observed in 21.2% (39 out of 184) cases. Lymphocyte-predominant tumors showed statistically significant expression of PD-L1 in both tumor (P < 0.0001) and immune cells (P 0.036). On univariate analysis, PD-L1 in immune cells was associated with good overall survival (P 0.05) as well as disease-free survival (P 0.013). On multivariate analysis, the same was associated with a significantly decreased risk for recurrence (P 0.018). CONCLUSION: PD-L1 expression in stromal immune cells proved to be a significant prognostic factor for TNBC. This data can serve as a baseline to plan clinical trials with anti-PD-L1 drugs for TNBC in the Indian setting.


Assuntos
Apoptose/efeitos dos fármacos , Antígeno B7-H1/uso terapêutico , Carcinoma/tratamento farmacológico , Imunoterapia/estatística & dados numéricos , Imunoterapia/normas , Ligantes , Neoplasias de Mama Triplo Negativas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Adulto Jovem
20.
In Vivo ; 35(6): 3067-3071, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34697138

RESUMO

BACKGROUND/AIM: Triple-negative matrix-producing breast carcinoma (MPBC) is rare, recalcitrant, and highly aggressive. The present study aimed to determine the efficacy of tumor-targeting leucine-arginine auxotroph Salmonella typhimurium (S. typhimurium) A1-R on a triple-negative MPBC in a patient-derived orthotopic xenograft (PDOX) model. MATERIALS AND METHODS: The PDOX MPBC model was established in the left second mammary gland of nude mice by surgical orthotopic implantation (SOI). PDOX models were randomized into two groups when the tumor volume reached over 70 mm3: a control group (n=6); and a tumor-targeting S. typhimurium A1-R group (n=7), [intravenous (i.v.) injection of S. typhimurium A1-R via the tail vein, weekly, for two weeks]. All mice were sacrificed on day 14. Tumor volume and body weight were measured once per week. RESULTS: S. typhimurium A1-R exquisitely targeted and arrested the growth of the MPBC PDOX compared to the control group (p=0.017). CONCLUSION: S. typhimurium A1-R has future clinical potential for triple-negative MPBC patients.


Assuntos
Salmonella typhimurium , Neoplasias de Mama Triplo Negativas , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Nus , Salmonella typhimurium/genética , Neoplasias de Mama Triplo Negativas/terapia , Ensaios Antitumorais Modelo de Xenoenxerto
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