RESUMEN
Monocytes and macrophages are major components of the tumor microenvironment, but their contributions to human cancer are poorly understood. We used molecular profiling combined with functional assays to investigate the role of these cells in human renal cell carcinoma (RCC). Blood monocytes from RCC patients displayed a tumor-promoting transcriptional profile that supported functions like angiogenesis and invasion. Induction of this protumor phenotype required an interleukin-1 receptor (IL-1R)-dependent mechanism. Indeed, targeting of IL-1-IL-1R axis in a human RCC xenograft model abrogated the protumor phenotype of tumor-associated macrophages (TAMs) and reduced tumor growth in vivo. Supporting this, meta-analysis of gene expression from human RCC tumors showed IL1B expression to correlate with myelomonocytic markers, protumor genes, and tumor staging. Analyzing RCC patient tumors confirmed the protumor phenotype of TAMs. These data provide direct evidence for a tumor-promoting role of monocytes and macrophages in human cancer and indicate IL-1-IL-1R as a possible therapeutic target.
Asunto(s)
Carcinoma de Células Renales/inmunología , Interleucina-1beta/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Receptores de Interleucina-1/inmunología , Animales , Proliferación Celular/genética , Citocinas/biosíntesis , Citocinas/inmunología , Perfilación de la Expresión Génica , Humanos , Inflamación/inmunología , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/biosíntesis , Interleucina-1beta/genética , Ratones , Ratones Noqueados , Ratones SCID , Factor 88 de Diferenciación Mieloide , Trasplante de Neoplasias , Neovascularización Patológica , Receptores de Interleucina-1/antagonistas & inhibidores , Receptores de Interleucina-1/genética , Factor de Transcripción ReIA/genética , Trasplante Heterólogo , Células Tumorales CultivadasRESUMEN
Immunotherapeutic approaches, including adoptive cell therapy, revolutionized treatment in multiple myeloma (MM). As dendritic cells (DCs) are professional antigen-presenting cells and key initiators of tumor-specific immune responses, DC-based immunotherapy represents an attractive therapeutic approach in cancer. The past years, various DC-based approaches, using particularly ex-vivo-generated monocyte-derived DCs, have been tested in preclinical and clinical MM studies. However, long-term and durable responses in MM patients were limited, potentially attributed to the source of monocyte-derived DCs and the immunosuppressive bone marrow microenvironment. In this review, we briefly summarize the DC development in the bone marrow niche and the phenotypical and functional characteristics of the major DC subsets. We address the known DC deficiencies in MM and give an overview of the DC-based vaccination protocols that were tested in MM patients. Lastly, we also provide strategies to improve the efficacy of DC vaccines using new, improved DC-based approaches and combination therapies for MM patients.
Asunto(s)
Células Dendríticas/inmunología , Inmunoterapia , Mieloma Múltiple/inmunología , Mieloma Múltiple/terapia , Animales , Antígenos de Neoplasias , Biomarcadores , Vacunas contra el Cáncer , Plasticidad de la Célula/inmunología , Toma de Decisiones Clínicas , Terapia Combinada , Células Dendríticas/metabolismo , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Humanos , Inmunomodulación , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/mortalidad , Resultado del Tratamiento , VacunaciónRESUMEN
Efficient priming of anti-tumor T cells requires the uptake and presentation of tumor antigens by immunogenic dendritic cells (DCs) and occurs mainly in lymph nodes draining the tumor (tdLNs). However, tumors expand and activate myeloid-derived suppressor cells (MDSCs) that inhibit CTL functions by several mechanisms. While the immune-suppressive nature of the tumor microenvironment is largely documented, it is not known whether similar immune-suppressive mechanisms operate in the tdLNs. In this study, we analyzed MDSC characteristics within tdLNs. We show that, in a metastasis-free context, MO-MDSCs are the dominant MDSC population within tdLNs, that they are highly suppressive and that tumor proximity enhances their recruitment to tdLN via a CCR2/CCL2-dependent pathway. Altogether our results uncover a mechanism by which tumors evade the immune system that involves MDSC-mediated recruitment to the tdLN and the inhibition of T-cell activation even before reaching the highly immunosuppressive tumor microenvironment.
Asunto(s)
Células Supresoras de Origen Mieloide/metabolismo , Receptores CCR2/metabolismo , Microambiente Tumoral/inmunología , Animales , Línea Celular Tumoral , Femenino , Humanos , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/fisiología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Monocitos/metabolismo , Células Mieloides/inmunología , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/fisiología , Neoplasias/inmunología , Receptores CCR2/inmunologíaRESUMEN
Tumors of various histological origins show abundant infiltration of myeloid cells from early stages of disease progression. These cells have a profound impact on antitumor immunity and influence fundamental processes that underlie malignancy, including neoangiogenesis, sustained cancer cell proliferation, metastasis and therapy resistance. For these reasons, development of therapeutic approaches to deplete or reprogram myeloid cells in cancer is an emerging field of interest. However, knowledge about the heterogeneity of myeloid cells in tumors and their variability between patients and disease stages is still limited. In this review, we summarize the most recent advances in our understanding about how the phenotype of tumor-associated macrophages, monocytes, neutrophils, myeloid-derived suppressor cells and dendritic cells is dictated by their ontogeny, activation status and localization. We also outline major open questions that will only be resolved by applying high-dimensional single-cell technologies and systems biology approaches in the analysis of the tumor microenvironment.
Asunto(s)
Proliferación Celular , Células Mieloides/inmunología , Neoplasias/inmunología , Microambiente Tumoral/inmunología , Animales , Células Dendríticas/inmunología , Humanos , Macrófagos/inmunología , Monocitos/inmunología , Células Mieloides/patología , Neoplasias/patología , Neutrófilos/inmunologíaRESUMEN
OBJECTIVE: Postoperative ileus (POI) is assumed to result from myeloid cells infiltrating the intestinal muscularis externa (ME) in patients undergoing abdominal surgery. In the current study, we investigated the role of infiltrating monocytes in a murine model of intestinal manipulation (IM)-induced POI in order to clarify whether monocytes mediate tissue damage and intestinal dysfunction or they are rather involved in the recovery of gastrointestinal (GI) motility. DESIGN: IM was performed in mice with defective monocyte migration to tissues (C-C motif chemokine receptor 2, Ccr2-/ - mice) and wild-type (WT) mice to study the role of monocytes and monocyte-derived macrophages (MΦs) during onset and resolution of ME inflammation. RESULTS: At early time points, IM-induced GI transit delay and inflammation were equal in WT and Ccr2 -/- mice. However, GI transit recovery after IM was significantly delayed in Ccr2 -/- mice compared with WT mice, associated with increased neutrophil-mediated immunopathology and persistent impaired neuromuscular function. During recovery, monocyte-derived MΦs acquire pro-resolving features that aided in the resolution of inflammation. In line, bone marrow reconstitution and treatment with MΦ colony-stimulating factor 1 enhanced monocyte recruitment and MΦ differentiation and ameliorated GI transit in Ccr2 -/- mice. CONCLUSION: Our study reveals a critical role for monocyte-derived MΦs in restoring intestinal homeostasis after surgical trauma. From a therapeutic point of view, our data indicate that inappropriate targeting of monocytes may increase neutrophil-mediated immunopathology and prolong the clinical outcome of POI, while future therapies should be aimed at enhancing MΦ physiological repair functions.
Asunto(s)
Ileus/inmunología , Ileus/patología , Macrófagos/inmunología , Monocitos/inmunología , Complicaciones Posoperatorias/inmunología , Complicaciones Posoperatorias/patología , Receptores CCR2/inmunología , Animales , Diferenciación Celular , Movimiento Celular , Modelos Animales de Enfermedad , Motilidad Gastrointestinal , Tránsito Gastrointestinal , Homeostasis/inmunología , Inflamación/inmunología , Inflamación/patología , Ratones , Músculo Liso/patologíaRESUMEN
The tumor-promoting role of macrophages has been firmly established in most cancer types. However, macrophage identity has been a matter of debate, since several levels of complexity result in considerable macrophage heterogeneity. Ontogenically, tissue-resident macrophages derive from yolk sac progenitors which either directly or via a fetal liver monocyte intermediate differentiate into distinct macrophage types during embryogenesis and are maintained throughout life, while a disruption of the steady state mobilizes monocytes and instructs the formation of monocyte-derived macrophages. Histologically, the macrophage phenotype is heavily influenced by the tissue microenvironment resulting in molecularly and functionally distinct macrophages in distinct organs. Finally, a change in the tissue microenvironment as a result of infectious or sterile inflammation instructs different modes of macrophage activation. These considerations are relevant in the context of tumors, which can be considered as sites of chronic sterile inflammation encompassing subregions with distinct environmental conditions (for example, hypoxic versus normoxic). Here, we discuss existing evidence on the role of macrophage subpopulations in steady state tissue and primary tumors of the breast, lung, pancreas, brain and liver.
Asunto(s)
Macrófagos/fisiología , Monocitos/citología , Neoplasias/inmunología , Microambiente Tumoral , Animales , HumanosRESUMEN
PURPOSE OF REVIEW: Tumors contain not only cancer cells but also nontransformed types of cells, the stromal cells. A bidirectional interplay exists between transformed and nontransformed cells leading to tumor progression and metastasis. Tumor-associated macrophages (TAMs) are the most abundant tumor-infiltrating leukocytes characterized by a high heterogeneity and plasticity. TAMs exhibit strong protumoral activities and are related to bad prognosis and worse overall survival in various cancer types. RECENT FINDINGS: Recent progress has delineated the existence of distinct TAM subsets in primary tumors and metastatic sites regulated by diverse mechanisms and triggering strong protumoral functions such as immunossuppression, angiogenesis, metastasis and resistance to current therapies. SUMMARY: Delineating the regulatory pathways governing TAM heterogeneity and activation could present a novel frontier in cancer therapy. TAM targeting/repolarization is considered as a promising novel therapeutic modality in combination with standard-of-care therapies or immuno checkpoint blockers.
Asunto(s)
Macrófagos/patología , Neoplasias/patología , Microambiente Tumoral , Animales , Transformación Celular Neoplásica , Progresión de la Enfermedad , HumanosRESUMEN
Monocytes consist of two well-defined subsets, the Ly6C+ and Ly6C- monocytes. Both CD11b+ myeloid cells populations have been proposed to infiltrate tissues during inflammation. While infiltration of Ly6C+ monocytes is an established pathogenic factor during hepatic inflammation, the role of Ly6C- monocytes remains elusive. Mice suffering experimental African trypanosome infection die from systemic inflammatory response syndrome (SIRS) that is initiated by phagocytosis of parasites by liver myeloid cells and culminates in apoptosis/necrosis of liver myeloid and parenchymal cells that reduces host survival. C57BL/6 mice are considered as trypanotolerant to Trypanosoma congolense infection. We have reported that in these animals, IL-10, produced among others by myeloid cells, limits the liver damage caused by pathogenic TNF-producing Ly6C+ monocytes, ensuring prolonged survival. Here, the heterogeneity and dynamics of liver myeloid cells in T. congolense-infected C57/BL6 mice was further dissected. Moreover, the contribution of Ly6C- monocytes to trypanotolerance was investigated. By using FACS analysis and adoptive transfer experiments, we found that the accumulation of Ly6C- monocytes and macrophages in the liver of infected mice coincided with a drop in the pool of Ly6C+ monocytes. Pathogenic TNF mainly originated from Ly6C+ monocytes while Ly6C- monocytes and macrophages were major and equipotent sources of IL-10 within myeloid cells. Moreover, Nr4a1 (Nur77) transcription factor-dependent Ly6C- monocytes exhibited IL-10-dependent and cell contact-dependent regulatory properties contributing to trypanotolerance by suppressing the production of TNF by Ly6C+ monocytes and by promoting the differentiation of the latter cells into macrophages. Thus, Ly6C- monocytes can dampen liver damage caused by an extensive Ly6C+ monocyte-associated inflammatory immune response in T. congolense trypanotolerant animals. In a more general context, Ly6C- or Ly6C+ monocyte targeting may represent a therapeutic approach in liver pathogenicity induced by chronic infection.
Asunto(s)
Antígenos Ly/inmunología , Diferenciación Celular , Inflamación/etiología , Hepatopatías/etiología , Macrófagos/inmunología , Monocitos/inmunología , Monocitos/patología , Tripanosomiasis Africana/inmunología , Animales , Apoptosis , Western Blotting , Proliferación Celular , Femenino , Citometría de Flujo , Técnicas para Inmunoenzimas , Inflamación/patología , Interleucina-10/genética , Interleucina-10/metabolismo , Hepatopatías/patología , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Células Mieloides/inmunología , Células Mieloides/patología , Fagocitosis , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Trypanosoma congolense/inmunología , Tripanosomiasis Africana/complicaciones , Tripanosomiasis Africana/parasitología , Células Tumorales CultivadasRESUMEN
The tumor stroma has long been ignored as therapeutic target, but it has become clear that several stromal cell types play a nonredundant role during tumor progression. In particular, macrophages possess the capacity to stimulate tumor growth and metastasis via multiple mechanisms. In this issue of the European Journal of Immunology, a study by Tymoszuk et al. Eur. J. Immunol. 2014. 44: 2247-2262 demonstrates that both monocyte recruitment and local macrophage proliferation determines the tumor-associated macrophage (TAM) pool size in HER2/Neu-driven mammary carcinomas. These tumors contain two main TAM subsets--MHC class II (MHC-II)(lo) F4/80(hi) and MHC-II(hi) F4/80(lo)--similar to what was observed in other tumor models. Interestingly, only the MHC-II(lo) F4/80(hi) subset is largely absent in a STAT1-deficient background. STAT1 induces the expression of CSF-1, which in turn drives TAM proliferation and possibly also the M2 gene signature of MHC-II(lo) F4/80(hi) TAM. Conversely, STAT1 deficiency upregulates M2 gene expression in MHC-II(hi) F4/80(lo) TAM, demonstrating that both TAM subsets are differentially regulated, probably as a consequence of their distinct intratumoral localization. In this Commentary, we place these findings in the context of current knowledge and propose new avenues for future research.
Asunto(s)
Macrófagos/inmunología , Macrófagos/metabolismo , Factor de Transcripción STAT1/metabolismo , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Proliferación Celular , Femenino , Genes MHC Clase II/inmunología , Humanos , Factor Estimulante de Colonias de Macrófagos/inmunología , Factor Estimulante de Colonias de Macrófagos/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Receptor ErbB-2/metabolismo , Factor de Transcripción STAT1/inmunologíaRESUMEN
Chemotherapy has been a standard treatment for cancer for the past several decades and has long been suspected to cause systemic immune suppression. However, in recent years it has become clear that the immune status of a patient is an independent prognostic factor for chemotherapeutic efficacy, and that T-cell-mediated responses actively contribute to the tumor destruction triggered by some chemotherapeutic agents. In this respect, the induction of immunogenic cell death by these compounds appears to be crucial. In this issue of the European Journal of Immunology, a study by Hannesdóttir et al. [Eur. J. Immunol. 2013. 43: 2718-2729] demonstrates a crucial role for the IFN signaling molecule STAT1 during doxorubicin and Lapatinib treatment of HER2/Neu-driven mammary carcinomas. The genotoxic anthracycline doxorubicin causes immunogenic cancer cell death and is expected to depend on the immune system, but the dual ErbB2/HER2/Neu and ErbB1/EGFR inhibitor Lapatinib also turns out to cause immune reactivity. Although CD8⺠T cells are partially involved in this phenomenon, doxorubicin, and Lapatinib also affect the myeloid infiltrate (i.e. tumor-associated macrophages and monocytes) in tumors. In this Commentary, we place these findings in the context of current knowledge and propose new avenues for future research.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Linfocitos T CD8-positivos/efectos de los fármacos , Doxorrubicina/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinazolinas/administración & dosificación , Factor de Transcripción STAT1/metabolismo , Animales , Femenino , Humanos , LapatinibRESUMEN
Tumor growth coincides with an accumulation of myeloid-derived suppressor cells (MDSCs), which exert immune suppression and which consist of two main subpopulations, known as monocytic (MO) CD11b(+) CD115(+) Ly6G(-) Ly6C(high) MDSCs and granulocytic CD11b(+) CD115(-) Ly6G(+) Ly6C(int) polymorphonuclear (PMN)-MDSCs. However, whether these distinct MDSC subsets hamper all aspects of early CD8(+) T-cell activation--including cytokine production, surface marker expression, survival, and cytotoxicity--is currently unclear. Here, employing an in vitro coculture system, we demonstrate that splenic MDSC subsets suppress antigen-driven CD8(+) T-cell proliferation, but differ in their dependency on IFN-γ, STAT-1, IRF-1, and NO to do so. Moreover, MO-MDSC and PMN-MDSCs diminish IL-2 levels, but only MO-MDSCs affect IL-2Rα (CD25) expression and STAT-5 signaling. Unexpectedly, however, both MDSC populations stimulate IFN-γ production by CD8(+) T cells on a per cell basis, illustrating that some T-cell activation characteristics are actually stimulated by MDSCs. Conversely, MO-MDSCs counteract the activation-induced change in CD44, CD62L, CD162, and granzyme B expression, while promoting CD69 and Fas upregulation. Together, these effects result in an altered CD8(+) T-cell adhesiveness to the extracellular matrix and selectins, sensitivity to FasL-mediated apoptosis, and cytotoxicity. Hence, MDSCs intricately influence different CD8(+) T-cell activation events in vitro, whereby some parameters are suppressed while others are stimulated.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Activación de Linfocitos/inmunología , Células Mieloides/inmunología , Neoplasias/inmunología , Animales , Antígenos CD/biosíntesis , Antígenos de Diferenciación de Linfocitos T/biosíntesis , Antígenos Ly/metabolismo , Apoptosis/inmunología , Antígeno CD11b/metabolismo , Adhesión Celular/inmunología , Línea Celular , Proliferación Celular , Femenino , Granzimas/biosíntesis , Receptores de Hialuranos/biosíntesis , Factor 1 Regulador del Interferón , Interferón gamma/biosíntesis , Interleucina-2/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Selectina L/biosíntesis , Lectinas Tipo C/biosíntesis , Glicoproteínas de Membrana/biosíntesis , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/inmunología , Óxido Nítrico/metabolismo , Receptor de Factor Estimulante de Colonias de Macrófagos/metabolismo , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT5/metabolismo , Transducción de Señal/inmunología , Regulación hacia Arriba , Receptor fas/biosíntesisRESUMEN
Immune checkpoint inhibitor (ICI) therapy has proven revolutionary in the treatment of some cancers. However, ovarian cancer remains unresponsive to current leading ICIs, such as anti-PD1 or anti-PD-L1. In this article, we explored the potential of an upcoming checkpoint molecule, T-cell immunoglobulin and mucin domain 3 (TIM3), for the treatment of ovarian cancer using a syngeneic orthotopic mouse model (ID8-fLuc). Besides therapeutic efficacy, we focused on exploring immune changes in tumor tissue and peritoneal fluid. Our results showed no improvement in survival in ovarian cancer-bearing mice after anti-TIM3 treatment when used as monotherapy nor when combined with anti-PD1 or standard-of-care chemotherapy (carboplatin/paclitaxel). This was reflected in the unaltered immune infiltration in treated mice compared to control mice. Altering the order of drug administration within the combination treatment altered the survival results, but did not result in a survival benefit over chemotherapy alone. These findings highlight the need for further preclinical studies to find beneficial treatment schemes and combination therapies for ovarian cancer.
RESUMEN
Cancer vaccines aim at generating cytotoxic CD8+ T cells that kill cancer cells and confer durable tumor regression. Hereto, CD8+ peptide epitopes should be presented by antigen presenting cells to CD8+ T cells in lymphoid tissue. Unfortunately, in unformulated soluble form, peptide antigens are poorly taken up by antigen presenting cells and do not efficiently reach lymph nodes. Hence, the lack of efficient delivery remains a major limitation for successful clinical translation of cancer vaccination using peptide antigens. Here we propose a generic peptide nanoformulation strategy by extending the amino acid sequence of the peptide antigen epitope with 10 glutamic acid residues. The resulting overall anionic charge of the peptide allows encapsulation into lipid nanoparticles (peptide-LNP) by electrostatic interaction with an ionizable cationic lipid. We demonstrate that intravenous injection of peptide-LNP efficiently delivers the peptide to immune cells in the spleen. Peptide-LNP that co-encapsulate an imidazoquinoline TLR7/8 agonist (IMDQ) induce robust innate immune activation in a broad range of immune cell subsets in the spleen. Peptide-LNP containing the minimal CD8+ T cell epitope of the HPV type 16 E7 oncoprotein and IMDQ induces high levels of antigen-specific CD8+ T cells in the blood, and can confer protective immunity against E7-expressing tumors in both prophylactic and therapeutic settings.
Asunto(s)
Ratones Endogámicos C57BL , Nanopartículas , Receptor Toll-Like 7 , Receptor Toll-Like 8 , Animales , Nanopartículas/química , Receptor Toll-Like 7/agonistas , Receptor Toll-Like 8/agonistas , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/administración & dosificación , Ratones , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Lípidos/química , Péptidos/química , Femenino , Proteínas E7 de Papillomavirus/inmunología , Quinolinas/farmacología , Quinolinas/química , Imidazoles/química , Imidazoles/farmacologíaRESUMEN
Conventional dendritic cells (cDCs) are at the forefront of activating the immune system to mount an anti-tumor immune response. Flt3L is a cytokine required for DC development that can increase DC abundance in the tumor when administered therapeutically. However, the impact of Flt3L on the phenotype of distinct cDC subsets in the tumor microenvironment is still largely undetermined. Here, using multi-omic single-cell analysis, we show that Flt3L therapy increases all cDC subsets in orthotopic E0771 and TS/A breast cancer and LLC lung cancer models, but this did not result in a reduction of tumor growth in any of the models. Interestingly, a CD81+migcDC1 population, likely developing from cDC1, was induced upon Flt3L treatment in E0771 tumors as well as in TS/A breast and LLC lung tumors. This CD81+migcDC1 subset is characterized by the expression of both canonical cDC1 markers as well as migratory cDC activation and regulatory markers and displayed a Treg-inducing potential. To shift the cDC phenotype towards a T-cell stimulatory phenotype, CD40 agonist therapy was administered to E0771 tumor-bearing mice in combination with Flt3L. However, while αCD40 reduced tumor growth, Flt3L failed to improve the therapeutic response to αCD40 therapy. Interestingly, Flt3L+αCD40 combination therapy increased the abundance of Treg-promoting CD81+migcDC1. Nonetheless, while Treg-depletion and αCD40 therapy were synergistic, the addition of Flt3L to this combination did not result in any added benefit. Overall, these results indicate that merely increasing cDCs in the tumor by Flt3L treatment cannot improve anti-tumor responses and therefore might not be beneficial for the treatment of cancer, though could still be of use to increase cDC numbers for autologous DC-therapy.
Asunto(s)
Neoplasias Pulmonares , Linfocitos T Reguladores , Animales , Ratones , Receptores CCR7 , Neoplasias Pulmonares/tratamiento farmacológico , Terapia Combinada , Antígenos CD40 , Microambiente TumoralRESUMEN
Recruiting endogenous antibodies to the surface of cancer cells using antibody-recruiting molecules has the potential to unleash innate immune effector killing mechanisms against antibody-bound cancer cells. The affinity of endogenous antibodies is relatively low, and many currently explored antibody-recruiting strategies rely on targeting over-expressed receptors, which have not yet been identified in most solid tumors. Here, both challenges are addressed by functionalizing poly(propyleneimine) (PPI) dendrimers with both multiple dinitrophenyl (DNP) motifs, as anti-hapten antibody-recruiting motifs, and myristoyl motifs, as universal phospholipid cell membrane anchoring motifs, to recruit anti-hapten antibodies to cell surfaces. By exploiting the multivalency of the ligand exposure on the dendrimer scaffold, it is demonstrated that dendrimers featuring ten myristoyl and six DNP motifs exhibit the highest antibody-recruiting capacity in vitro. Furthermore, it is shown that treating cancer cells with these dendrimers in vitro marks them for phagocytosis by macrophages in the presence of anti-hapten antibodies. As a proof-of-concept, it is shown that intratumoral injection of these dendrimers in vivo in tumor-bearing mice results in the recruitment of anti-DNP antibodies to the cell surface in the tumor microenvironment. These findings highlight the potential of dendrimers as a promising class of novel antibody-recruiting molecules for use in cancer immunotherapy.
Asunto(s)
Dendrímeros , Animales , Ratones , Anticuerpos , Haptenos , Fagocitosis , Dinitrobencenos , Membrana CelularRESUMEN
Macrophages are diverse immune cells populating all tissues and adopting a unique tissue-specific identity. Breast macrophages play an essential role in the development and function of the mammary gland over one's lifetime. In the recent years, with the development of fate-mapping, imaging and scRNA-seq technologies we grew a better understanding of the origin, heterogeneity and function of mammary macrophages in homeostasis but also during breast cancer development. Here, we aim to provide a comprehensive review of the latest improvements in studying the macrophage heterogeneity in healthy mammary tissues and breast cancer.
Asunto(s)
Neoplasias de la Mama , Macrófagos , Femenino , Homeostasis , HumanosRESUMEN
Ovarian cancer (OC) is the deadliest gynecological malignancy in developed countries and is the seventh-highest cause of death in women diagnosed with cancer worldwide. Currently, several therapies are in use against OC, including debulking surgery, chemotherapy, as well as targeted therapies. Even though the current standard-of-care therapies improve survival, a vast majority of OC patients relapse. Additionally, immunotherapies have only resulted in meager patient outcomes, potentially owing to the intricate immunosuppressive nexus within the tumor microenvironment. In this scenario, dendritic cell (DC) vaccination could serve as a potential addition to the therapeutic options available against OC. In this review, we provide an overview of current therapies in OC, focusing on immunotherapies. Next, we highlight the potential of using DC vaccines in OC by underscoring the different DC subsets and their functions in OC. Finally, we provide an overview of the advances and pitfalls of current DC vaccine strategies in OC while providing future perspectives that could improve patient outcomes.
RESUMEN
Tumour-associated macrophages (TAMs) are essential players in the tumour microenvironment (TME) and modulate various pro-tumorigenic functions such as immunosuppression, angiogenesis, cancer cell proliferation, invasion and metastasis, along with resistance to anti-cancer therapies. TAMs also mediate important anti-tumour functions and can clear dying cancer cells via efferocytosis. Thus, not surprisingly, TAMs exhibit heterogeneous activities and functional plasticity depending on the type and context of cancer cell death that they are faced with. This ultimately governs both the pro-tumorigenic and anti-tumorigenic activity of TAMs, making the interface between TAMs and dying cancer cells very important for modulating cancer growth and the efficacy of chemo-radiotherapy or immunotherapy. In this review, we discuss the interface of TAMs with cancer cell death from the perspectives of cell death pathways, TME-driven variations, TAM heterogeneity and cell-death-inducing anti-cancer therapies. We believe that a better understanding of how dying cancer cells influence TAMs can lead to improved combinatorial anti-cancer therapies, especially in combination with TAM-targeting immunotherapies.
Asunto(s)
Neoplasias , Macrófagos Asociados a Tumores , Humanos , Macrófagos/metabolismo , Microambiente Tumoral , Neoplasias/metabolismo , InmunoterapiaRESUMEN
Junctional adhesion molecule-A (JAM-A), expressed on the surface of myeloid cells, is required for extravasation at sites of inflammation and may also modulate myeloid cell activation. Infiltration of myeloid cells is a common feature of tumors that drives disease progression, but the function of JAM-A in this phenomenon and its impact on tumor-infiltrating myeloid cells is little understood. Here we show that systemic cancer-associated inflammation in mice enhanced JAM-A expression selectively on circulating monocytes in an IL1ß-dependent manner. Using myeloid-specific JAM-A-deficient mice, we found that JAM-A was dispensable for recruitment of monocytes and other myeloid cells to tumors, in contrast to its reported role in inflammation. Single-cell RNA sequencing revealed that loss of JAM-A did not influence the transcriptional reprogramming of myeloid cells in the tumor microenvironment. Overall, our results support the notion that cancer-associated inflammation can modulate the phenotype of circulating immune cells, and we demonstrate that tumors can bypass the requirement of JAM-A for myeloid cell recruitment and reprogramming.
Asunto(s)
Molécula A de Adhesión de Unión , Ratones , Animales , Microambiente Tumoral/genética , Células Mieloides/metabolismo , Monocitos/metabolismo , Inflamación/metabolismoRESUMEN
Agonistic αCD40 therapy has been shown to inhibit cancer progression in only a fraction of patients. Understanding the cancer cell-intrinsic and microenvironmental determinants of αCD40 therapy response is therefore crucial to identify responsive patient populations and to design efficient combinatorial treatments. Here, we show that the therapeutic efficacy of αCD40 in subcutaneous melanoma relies on preexisting, type 1 classical dendritic cell (cDC1)-primed CD8+ T cells. However, after administration of αCD40, cDC1s were dispensable for antitumor efficacy. Instead, the abundance of activated cDCs, potentially derived from cDC2 cells, increased and further activated antitumor CD8+ T cells. Hence, distinct cDC subsets contributed to the induction of αCD40 responses. In contrast, lung carcinomas, characterized by a high abundance of macrophages, were resistant to αCD40 therapy. Combining αCD40 therapy with macrophage depletion led to tumor growth inhibition only in the presence of strong neoantigens. Accordingly, treatment with immunogenic cell death-inducing chemotherapy sensitized lung tumors to αCD40 therapy in subcutaneous and orthotopic settings. These insights into the microenvironmental regulators of response to αCD40 suggest that different tumor types would benefit from different combinations of therapies to optimize the clinical application of CD40 agonists. SIGNIFICANCE: This work highlights the temporal roles of different dendritic cell subsets in promoting CD8+ T-cell-driven responses to CD40 agonist therapy in cancer.