RESUMO
Breast cancer poses one of the largest threats to women's health. Treatment continues to improve for all the subtypes of breast cancer, but some subtypes, such as triple negative breast cancer, still present a significant treatment challenge. Additionally, metastasis and local recurrence are two prevalent problems in breast cancer treatment. A newer type of therapy, immunotherapy, may offer alternatives to traditional treatments for difficult-to-treat subtypes. Immunotherapy engages the host's immune system to eradicate disease, with the potential to induce long-lasting, durable responses. However, systemic immunotherapy is only approved in a limited number of indications, and it benefits only a minority of patients. Furthermore, immune related toxicities following systemic administration of potent immunomodulators limit dosing and, consequently, efficacy. To address these safety considerations and improve treatment efficacy, interest in local delivery at the site of the tumor has increased. Numerous intratumorally delivered immunotherapeutics have been and are being explored clinically and preclinically, including monoclonal antibodies, cellular therapies, viruses, nucleic acids, cytokines, innate immune agonists, and bacteria. This review summarizes the current and past intratumoral immunotherapy clinical landscape in breast cancer as well as current progress that has been made in preclinical studies, with a focus on delivery parameters and considerations.
Assuntos
Neoplasias da Mama , Imunoterapia , Humanos , Feminino , Neoplasias da Mama/terapia , Neoplasias da Mama/imunologia , Imunoterapia/métodos , AnimaisRESUMO
Mammalian aging is associated with multiple defects of hematopoiesis, most prominently with the impaired development of T and B lymphocytes. This defect is thought to originate in hematopoietic stem cells (HSCs) of the bone marrow, specifically due to the age-dependent accumulation of HSCs with preferential megakaryocytic and/or myeloid potential ("myeloid bias"). Here, we tested this notion using inducible genetic labeling and tracing of HSCs in unmanipulated animals. We found that the endogenous HSC population in old mice shows reduced differentiation into all lineages including lymphoid, myeloid, and megakaryocytic. Single-cell RNA sequencing and immunophenotyping (CITE-Seq) showed that HSC progeny in old animals comprised balanced lineage spectrum including lymphoid progenitors. Lineage tracing using the aging-induced HSC marker Aldh1a1 confirmed the low contribution of old HSCs across all lineages. Competitive transplantations of total bone marrow cells with genetically marked HSCs revealed that the contribution of old HSCs was reduced, but compensated by other donor cells in myeloid cells but not in lymphocytes. Thus, the HSC population in old animals becomes globally decoupled from hematopoiesis, which cannot be compensated in lymphoid lineages. We propose that this partially compensated decoupling, rather than myeloid bias, is the primary cause of the selective impairment of lymphopoiesis in older mice.
Assuntos
Envelhecimento , Células-Tronco Hematopoéticas , Camundongos , Animais , Linhagem da Célula , Diferenciação Celular , Medula Óssea , Hematopoese , MamíferosRESUMO
The development of immunotherapy agents has revolutionized the field of oncology. The only FDA-approved immunotherapeutic approach in breast cancer consists of immune checkpoint inhibitors, yet several novel immune-modulatory strategies are being actively studied and appear promising. Innovative immunotherapeutic strategies are urgently needed in triple negative breast cancer (TNBC), a subtype of breast cancer known for its poor prognosis and its resistance to conventional treatments. TNBC is more primed to respond to immunotherapy given the presence of more tumor infiltrating lymphocytes, higher PD-L1 expression, and higher tumor mutation burden relative to the other breast cancer subtypes, and therefore, immuno-oncology represents a key area of promise for TNBC research. The aim of this review is to highlight current data and ongoing efforts to establish the safety and efficacy of immunotherapeutic approaches beyond checkpoint inhibitors in TNBC.
RESUMO
Developmental origins of dendritic cells (DCs) including conventional DCs (cDCs, comprising cDC1 and cDC2 subsets) and plasmacytoid DCs (pDCs) remain unclear. We studied DC development in unmanipulated adult mice using inducible lineage tracing combined with clonal DNA "barcoding" and single-cell transcriptome and phenotype analysis (CITE-seq). Inducible tracing of Cx3cr1+ hematopoietic progenitors in the bone marrow showed that they simultaneously produce all DC subsets including pDCs, cDC1s, and cDC2s. Clonal tracing of hematopoietic stem cells (HSCs) and of Cx3cr1+ progenitors revealed clone sharing between cDC1s and pDCs, but not between the two cDC subsets or between pDCs and B cells. Accordingly, CITE-seq analyses of differentiating HSCs and Cx3cr1+ progenitors identified progressive stages of pDC development including Cx3cr1+ Ly-6D+ pro-pDCs that were distinct from lymphoid progenitors. These results reveal the shared origin of pDCs and cDCs and suggest a revised scheme of DC development whereby pDCs share clonal relationship with cDC1s.
Assuntos
Linfócitos B , Células Dendríticas , Animais , Contagem de Células , Coreia , Células-Tronco Hematopoéticas , CamundongosAssuntos
COVID-19 , Ensaios Clínicos como Assunto , Término Precoce de Ensaios Clínicos , Oncologia/métodos , Neoplasias/terapia , Pesquisa Biomédica/organização & administração , Pesquisa Biomédica/tendências , COVID-19/epidemiologia , COVID-19/prevenção & controle , Ensaios Clínicos como Assunto/classificação , Ensaios Clínicos como Assunto/organização & administração , Ensaios Clínicos como Assunto/estatística & dados numéricos , Controle de Doenças Transmissíveis/métodos , Término Precoce de Ensaios Clínicos/efeitos adversos , Término Precoce de Ensaios Clínicos/estatística & dados numéricos , Previsões , Humanos , Estudos Observacionais como Assunto/estatística & dados numéricos , SARS-CoV-2Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Neoplasias/imunologia , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Monoclonais/imunologia , Ensaios Clínicos como Assunto , Humanos , Neoplasias/metabolismoRESUMO
Adult mammalian hematopoietic stem cells (HSCs) reside in the bone marrow (BM) but can be mobilized into blood for use in transplantation. HSCs interact with BM niche cells that produce growth factor c-Kit ligand (Kitl/SCF) and chemokine CXCL12, and were thought to be static and sessile. We used two-photon laser scanning microscopy to visualize genetically labeled HSCs in the BM of live mice for several hours. The majority of HSCs showed a dynamic non-spherical morphology and significant motility, undergoing slow processive motion interrupted by short stretches of confined motion. HSCs moved in the perivascular space and showed intermittent close contacts with SCF-expressing perivascular stromal cells. In contrast, mobilization-inducing blockade of CXCL12 receptor CXCR4 and integrins rapidly abrogated HSC motility and shape dynamics in real time. Our results reveal an unexpectedly dynamic nature of HSC residence in the BM and interaction with the SCF+ stromal niche, which is disrupted during HSC mobilization.
Assuntos
Medula Óssea , Células-Tronco Hematopoéticas , Animais , Células da Medula Óssea , Movimento Celular , Quimiocina CXCL12 , Microscopia Intravital , Camundongos , Nicho de Células-TroncoRESUMO
The generation of all blood cell lineages (hematopoiesis) is sustained throughout the entire life span of adult mammals. Studies using cell transplantation identified the self-renewing, multipotent hematopoietic stem cells (HSCs) as the source of hematopoiesis in adoptive hosts and delineated a hierarchy of HSC-derived progenitors that ultimately yield mature blood cells. However, much less is known about adult hematopoiesis as it occurs in native hosts, i.e., without transplantation. Here we review recent advances in our understanding of native hematopoiesis, focusing in particular on the application of genetic lineage tracing in mice. The emerging evidence has established HSCs as the major source of native hematopoiesis, helped to define the kinetics of HSC differentiation, and begun exploring native hematopoiesis in stress conditions such as aging and inflammation. Major outstanding questions about native hematopoiesis still remain, such as its clonal composition, the nature of lineage commitment, and the dynamics of the process in humans.
Assuntos
Linhagem da Célula , Hematopoese , Adulto , Envelhecimento/fisiologia , Diferenciação Celular , Células-Tronco Hematopoéticas/citologia , Humanos , CinéticaRESUMO
Adult hematopoiesis has been studied in terms of progenitor differentiation potentials, whereas its kinetics in vivo is poorly understood. We combined inducible lineage tracing of endogenous adult hematopoietic stem cells (HSCs) with flow cytometry and single-cell RNA sequencing to characterize early steps of hematopoietic differentiation in the steady-state. Labeled cells, comprising primarily long-term HSCs and some short-term HSCs, produced megakaryocytic lineage progeny within 1 wk in a process that required only two to three cell divisions. Erythroid and myeloid progeny emerged simultaneously by 2 wk and included a progenitor population with expression features of both lineages. Myeloid progenitors at this stage showed diversification into granulocytic, monocytic, and dendritic cell types, and rare intermediate cell states could be detected. In contrast, lymphoid differentiation was virtually absent within the first 3 wk of tracing. These results show that continuous differentiation of HSCs rapidly produces major hematopoietic lineages and cell types and reveal fundamental kinetic differences between megakaryocytic, erythroid, myeloid, and lymphoid differentiation.
Assuntos
Células-Tronco Adultas/imunologia , Diferenciação Celular/imunologia , Divisão Celular/imunologia , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Adultas/citologia , Animais , Células Dendríticas/citologia , Células Dendríticas/imunologia , Granulócitos/citologia , Granulócitos/imunologia , Células-Tronco Hematopoéticas/citologia , Cinética , Megacariócitos/citologia , Megacariócitos/imunologia , Camundongos , Camundongos Transgênicos , Monócitos/citologia , Monócitos/imunologiaRESUMO
The production of blood cells is dependent on the activity of a rare stem cell population that normally resides in the bone marrow (BM) of the organism. These hematopoietic stem cells (HSCs) have the ability to both self-renew and differentiate, ensuring this lifelong hematopoiesis. Determining the regulation of HSC functions should thus provide critical insight to advancing regenerative medicine. Until quite recently, HSCs were primarily studied using in vitro studies and transplantations into immunodeficient hosts. Indeed, the definition of a bona fide HSC is its ability to reconstitute lymphopenic hosts. In this review, we discuss the development of novel, HSC-specific genetic reporter systems that enable the prospective identification of HSCs and the study of their functions in the absence of transplantation. Coupled with additional technological advances, these studies are now defining the fundamental properties of HSCs in vivo. Furthermore, complex cellular and molecular mechanisms that regulate HSC dormancy, self-renewal, and differentiation are being identified and further dissected. These novel reporter systems represent a major technological advance for the stem cell field and allow new questions to be addressed.