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1.
Immunity ; 38(6): 1236-49, 2013 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-23809164

RESUMO

Tumor progression is accompanied by an altered myelopoiesis causing the accumulation of immunosuppressive cells. Here, we showed that miR-142-3p downregulation promoted macrophage differentiation and determined the acquisition of their immunosuppressive function in tumor. Tumor-released cytokines signaling through gp130, the common subunit of the interleukin-6 cytokine receptor family, induced the LAP∗ isoform of C/EBPß transcription factor, promoting macrophage generation. miR-142-3p downregulated gp130 by canonical binding to its messenger RNA (mRNA) 3' UTR and repressed C/EBPß LAP∗ by noncanonical binding to its 5' mRNA coding sequence. Enforced miR expression impaired macrophage differentiation both in vitro and in vivo. Mice constitutively expressing miR-142-3p in the bone marrow showed a marked increase in survival following immunotherapy with tumor-specific T lymphocytes. By modulating a specific miR in bone marrow precursors, we thus demonstrated the feasibility of altering tumor-induced macrophage differentiation as a potent tool to improve the efficacy of cancer immunotherapy.


Assuntos
Imunoterapia/métodos , Macrófagos/imunologia , MicroRNAs/metabolismo , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , RNA Mensageiro/metabolismo , Animais , Antígenos de Neoplasias/imunologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Diferenciação Celular/genética , Linhagem Celular Tumoral , Receptor gp130 de Citocina/metabolismo , Imunoterapia/tendências , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/genética , Mielopoese/genética , Neoplasias Experimentais/terapia , RNA Mensageiro/genética , Transdução de Sinais , Esteroide Isomerases/genética , Esteroide Isomerases/metabolismo , Linfócitos T/imunologia , Linfócitos T/transplante , Transgenes/genética , Evasão Tumoral
2.
Proc Natl Acad Sci U S A ; 115(17): E4041-E4050, 2018 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-29632196

RESUMO

In a large proportion of cancer patients, CD8 T cells are excluded from the vicinity of cancer cells. The inability of CD8 T cells to reach tumor cells is considered an important mechanism of resistance to cancer immunotherapy. We show that, in human lung squamous-cell carcinomas, exclusion of CD8 T cells from tumor islets is correlated with a poor clinical outcome and with a low lymphocyte motility, as assessed by dynamic imaging on fresh tumor slices. In the tumor stroma, macrophages mediate lymphocyte trapping by forming long-lasting interactions with CD8 T cells. Using a mouse tumor model with well-defined stromal and tumor cell areas, macrophages were depleted with PLX3397, an inhibitor of colony-stimulating factor-1 receptor (CSF-1R). Our results reveal that a CSF-1R blockade enhances CD8 T cell migration and infiltration into tumor islets. Although this treatment alone has minor effects on tumor growth, its combination with anti-PD-1 therapy further increases the accumulation of CD8 T cells in close contact with malignant cells and delays tumor progression. These data suggest that the reduction of macrophage-mediated T cell exclusion increases tumor surveillance by CD8 T cells and renders tumors more responsive to anti-PD-1 treatment.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Macrófagos/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Aminopiridinas/farmacologia , Animais , Linfócitos T CD8-Positivos/patologia , Carcinoma de Células Escamosas/patologia , Seguimentos , Macrófagos/patologia , Camundongos , Receptor de Morte Celular Programada 1/imunologia , Pirróis/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Receptor de Fator Estimulador de Colônias de Macrófagos/imunologia , Estudos Retrospectivos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Proc Natl Acad Sci U S A ; 115(29): E6826-E6835, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-29967180

RESUMO

Antibody-secreting plasma cells (PCs) arise rapidly during adaptive immunity to control infections. The early PCs are retained within the reactive lymphoid organ where their localization and homeostasis rely on extrinsic factors, presumably produced by local niche cells. While myeloid cells have been proposed to form those niches, the contribution by colocalizing stromal cells has remained unclear. Here, we characterized a subset of fibroblastic reticular cells (FRCs) that forms a dense meshwork throughout medullary cords of lymph nodes (LNs) where PCs reside. This medullary FRC type is shown to be anatomically, phenotypically, and functionally distinct from T zone FRCs, both in mice and humans. By using static and dynamic imaging approaches, we provide evidence that medullary FRCs are the main cell type in contact with PCs guiding them in their migration. Medullary FRCs also represent a major local source of the PC survival factors IL-6, BAFF, and CXCL12, besides also producing APRIL. In vitro, medullary FRCs alone or in combination with macrophages promote PC survival while other LN cell types do not have this property. Thus, we propose that this FRC subset, together with medullary macrophages, forms PC survival niches within the LN medulla, and thereby helps in promoting the rapid development of humoral immunity, which is critical in limiting early pathogen spread.


Assuntos
Formação de Anticorpos , Homeostase/imunologia , Linfonodos/imunologia , Plasmócitos/imunologia , Animais , Fator Ativador de Células B/imunologia , Quimiocina CXCL12/imunologia , Interleucina-6/imunologia , Linfonodos/citologia , Masculino , Camundongos , Plasmócitos/citologia , Células Estromais/citologia , Células Estromais/imunologia
4.
J Immunol ; 199(6): 1998-2007, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28779024

RESUMO

So far, peripheral T cells have mostly been described to circulate between blood, secondary lymphoid organs (SLOs), and lymph in the steady state. This nomadic existence would allow them to accomplish their surveying task for both foreign Ags and survival signals. Although it is now well established that γδ T cells can be rapidly recruited to inflammatory sites or in certain tumor microenvironments, the trafficking properties of peripheral γδ T cells have been poorly studied in the steady state. In the present study, we highlight the existence of resident γδ T cells in the SLOs of specific pathogen-free mice. Indeed, using several experimental approaches such as the injection of integrin-neutralizing Abs that inhibit the entry of circulating lymphocytes into lymph nodes and long-term parabiosis experiments, we have found that, contrary to Ly-6C-/+CD44lo and Ly-6C+CD44hi γδ T cells, a significant proportion of Ly-6C-CD44hi γδ T cells are trapped for long periods of time within lymph nodes and the spleen in the steady state. Specific in vivo cell depletion strategies have allowed us to demonstrate that macrophages are the main actors involved in this long-term retention of Ly-6C-CD44hi γδ T cells in SLOs.


Assuntos
Linfonodos/imunologia , Macrófagos/imunologia , Baço/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Animais , Antígenos Ly/metabolismo , Comunicação Celular , Movimento Celular , Células Cultivadas , Receptores de Hialuronatos/metabolismo , Imunidade Inata , Vigilância Imunológica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo
5.
Cell Mol Life Sci ; 70(23): 4431-48, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23649148

RESUMO

The migration of T cells and access to tumor antigens is of utmost importance for the induction of protective anti-tumor immunity. Once having entered a malignant site, T cells encounter a complex environment composed of non-tumor cells along with the extracellular matrix (ECM). It is now well accepted that a deregulated ECM favors tumor progression and metastasis. Recent progress in imaging technologies has also highlighted the impact of the matrix architecture found in solid tumor on immune cells and especially T cells. In this review, we argue that the ability of T cells to mount an antitumor response is dependent on the matrix structure, more precisely on the balance between pro-migratory reticular fiber networks and unfavorable migration zones composed of dense and aligned ECM structures. Thus, the matrix architecture, that has long been considered to merely provide the structural framework of connective tissues, can play a key role in facilitating or suppressing the antitumor immune surveillance. A new challenge in cancer therapy will be to develop approaches aimed at altering the architecture of the tumor stroma, rendering it more permissive to antitumor T cells.


Assuntos
Matriz Extracelular/imunologia , Vigilância Imunológica/imunologia , Neoplasias/imunologia , Linfócitos T/imunologia , Animais , Movimento Celular/imunologia , Progressão da Doença , Matriz Extracelular/metabolismo , Humanos , Modelos Imunológicos , Metástase Neoplásica , Neoplasias/metabolismo , Neoplasias/patologia , Linfócitos T/citologia , Linfócitos T/metabolismo
6.
Cells ; 13(11)2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38891109

RESUMO

Chondrosarcoma (ChS), a malignant cartilage-producing tumor, is the second most frequently diagnosed osseous sarcoma after osteosarcoma. It represents a very heterogeneous group of malignant chemo- and radiation-resistant neoplasms, accounting for approximately 20% of all bone sarcomas. The majority of ChS patients have a good prognosis after a complete surgical resection, as these tumors grow slowly and rarely metastasize. Conversely, patients with inoperable disease, due to the tumor location, size, or metastases, represent a great clinical challenge. Despite several genetic and epigenetic alterations that have been described in distinct ChS subtypes, very few therapeutic options are currently available for ChS patients. Therefore, new prognostic factors for tumor progression as well as new treatment options have to be explored, especially for patients with unresectable or metastatic disease. Recent studies have shown that a correlation between immune infiltrate composition, tumor aggressiveness, and survival does exist in ChS patients. In addition, the intra-tumor microvessel density has been proven to be associated with aggressive clinical behavior and a high metastatic potential in ChS. This review will provide an insight into the ChS microenvironment, since immunotherapy and antiangiogenic agents are emerging as interesting therapeutic options for ChS patients.


Assuntos
Condrossarcoma , Microambiente Tumoral , Humanos , Condrossarcoma/patologia , Condrossarcoma/genética , Condrossarcoma/metabolismo , Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/genética , Imunoterapia , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/farmacologia
7.
Cancer Metastasis Rev ; 30(1): 27-43, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21267772

RESUMO

Tumour development is accompanied by an enhanced haematopoiesis. This is not a widespread activation since only cells belonging to the myelo-monocytic compartment are expanded and mobilized from primary sites of haematopoiesis to other organs, reaching also the tumour stroma. This process occurs early during tumour formation but becomes more evident in advanced disease. Far from being a simple, unwanted consequence of cancer development, accumulation of myelo-monocytitc cells plays a role in tumour vascularization, local spreading, establishment of metastasis at distant sites, and contribute to create an environment unfavourable for the adoptive immunity against tumour-associated antigens. Myeloid populations involved in these process are likely different but many cells, expanded in primary and secondary lymphoid organs of tumour-bearing mice, share various levels of the CD11b and Gr-1 (Ly6C/G) markers. CD11b(+)Gr-1(+) cells are currently named myeloid-derived suppressor cells for their ability to inhibit T lymphocyte responses in tumour-bearing hosts. In this manuscript, we review the recent literature on tumour-conditioned myeloid subsets that assist tumour growth, both in mice and humans.


Assuntos
Células Mieloides/citologia , Células Mieloides/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Animais , Humanos
8.
Blood ; 115(7): 1374-84, 2010 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-19903903

RESUMO

Telomerase reverse transcriptase (TERT) is a good candidate for cancer immunotherapy because it is overexpressed in 85% of all human tumors and implicated in maintenance of the transformed phenotype. TERT-based cancer vaccines have been shown to be safe, not inducing any immune-related pathology, but their impact on tumor progression is modest. Here we show that adoptive cell therapy with the use of high-avidity T lymphocytes reactive against telomerase can control the growth of different established tumors. Moreover, in transgenic adenocarcinoma mouse prostate mice, which develop prostate cancer, TERT-based adoptive cell therapy halted the progression to more aggressive and poorly differentiated tumors, significantly prolonging mouse survival. We also demonstrated that human tumors, including Burkitt lymphoma, and human cancer stem cells, are targeted in vivo by TERT-specific cytotoxic T lymphocytes. Effective therapy with T cells against telomerase, different from active vaccination, however, led to autoimmunity marked by a consistent, although transient, B-cell depletion in primary and secondary lymphoid organs, associated with alteration of the spleen cytoarchitecture. These results indicate B cells as an in vivo target of TERT-specific cytotoxic T lymphocytes during successful immunotherapy.


Assuntos
Adenocarcinoma/terapia , Transferência Adotiva/métodos , Linfopenia/patologia , Neoplasias da Próstata/terapia , Linfócitos T/transplante , Telomerase/imunologia , Adenocarcinoma/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Células da Medula Óssea/patologia , Vacinas Anticâncer , Linhagem Celular Tumoral , Neoplasias do Colo , Modelos Animais de Doenças , Antígeno HLA-A2/genética , Antígeno HLA-A2/imunologia , Neoplasias Pulmonares , Masculino , Melanoma , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transplante de Neoplasias , Neoplasias da Próstata/imunologia , Neoplasias Cutâneas , Baço/patologia , Linfócitos T/imunologia
9.
Cancers (Basel) ; 14(14)2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35884605

RESUMO

The essential roles endorsed by macrophages and monocytes are well established in response to infections, where they contribute to launching the differentiation of specific T-lymphocytes for long-term protection. This knowledge is the result of dynamic studies that can inspire the cancer field, particularly now that cancer immunotherapies elicit some tumor regression. Indeed, immune responses to cancer have mainly been studied after tumors have escaped immune attacks. In particular, the suppressive functions of macrophages were revealed in this context, introducing an obvious bias across the literature. In this review, we will focus on the ways inwhich monocytes and macrophages cooperate with T-lymphocytes, leading to successful immune responses. We will bring together the preclinical studies that have revealed the existence of such positive cooperation in the cancer field, and we will place particular emphasis on proposing the underlying mechanisms. Finally, we will give some perspectives to decipher the functional roles of such T-cell and myeloid cell interactions in the frame of human cancer immunotherapy.

10.
Eur J Immunol ; 40(1): 22-35, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19941314

RESUMO

CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSC) contribute to tumor immune evasion by restraining the activity of CD8+ T-cells. Two major MDSC subsets were recently shown to play an equal role in MDSC-induced immune dysfunctions: monocytic- and granulocytic-like. We isolated three fractions of MDSC, i.e. CD11b+/Gr-1high, CD11b+/Gr-1int, and CD11b+/Gr-1low populations that were characterized morphologically, phenotypically and functionally in different tumor models. In vitro assays showed that CD11b+/Gr-1int cell subset, mainly comprising monocytes and myeloid precursors, was always capable to suppress CD8+ T-cell activation, while CD11b+/Gr-1high cells, mostly granulocytes, exerted appreciable suppression only in some tumor models and when present in high numbers. The CD11b+/Gr-1int but not CD11b+/Gr-1high cells were also immunosuppressive in vivo following adoptive transfer. CD11b+/Gr-1low cells retained the immunosuppressive potential in most tumor models. Gene silencing experiments indicated that GM-CSF was necessary to induce preferential expansion of both CD11b+/Gr-1int and CD11b+/Gr-1low subsets in the spleen of tumor-bearing mice and mediate tumor-induced tolerance whereas G-CSF, which preferentially expanded CD11b+/Gr-1high cells, did not create such immunosuppressive environment. GM-CSF also acted on granulocyte-macrophage progenitors in the bone marrow inducing local expansion of CD11b+/Gr-1low cells. These data unveil a hierarchy of immunoregulatory activity among MDSC subsets that is controlled by tumor-released GM-CSF.


Assuntos
Antígeno CD11b/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Tolerância Imunológica , Células Mieloides/imunologia , Receptores de Quimiocinas/imunologia , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Mieloides/citologia , Transplante de Neoplasias , Neoplasias/imunologia , Interferência de RNA
11.
Front Immunol ; 11: 1590, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32793228

RESUMO

Immune checkpoint inhibitors are becoming standard treatments in several cancer types, profoundly changing the prognosis of a fraction of patients. Currently, many efforts are being made to predict responders and to understand how to overcome resistance in non-responders. Given the crucial role of myeloid cells as modulators of T effector cell function in tumors, it is essential to understand their impact on the clinical outcome of immune checkpoint blockade and on the mechanisms of immune evasion. In this review we focus on the existing clinical evidence of the relation between the presence of myeloid cell subsets and the response to anti-PD(L)1 and anti-CTLA-4 treatment. We highlight how circulating and tumor-infiltrating myeloid populations can be used as predictive biomarkers for immune checkpoint inhibitors in different human cancers, both at baseline and on treatment. Moreover, we propose to follow the dynamics of myeloid cells during immunotherapy as pharmacodynamic biomarkers. Finally, we provide an overview of the current strategies tested in the clinic that use myeloid cell targeting together with immune checkpoint blockade with the aim of uncovering the most promising approaches for effective combinations.


Assuntos
Biomarcadores , Inibidores de Checkpoint Imunológico/farmacologia , Proteínas de Checkpoint Imunológico/metabolismo , Células Mieloides/metabolismo , Animais , Estudos Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Terapia de Alvo Molecular , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Resultado do Tratamento
12.
Hum Vaccin Immunother ; 15(1): 189-192, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30192699

RESUMO

T cell-based immunotherapies have revolutionized the treatment against cancer. But complete and long-lasting efficacy is only observed in a fraction of the patient population. One of the suspected causes is the inability of cytotoxic T cells, endowed with tumor killing ability, to reach their malignant targets. Using dynamic fluorescence imaging to study the dynamic of T cells in tumors from patients with lung cancer, we have recently demonstrated that macrophages trap the T lymphocytes, which are not longer able to contact the tumor cells. In murine models of breast cancer, we could show that the depletion of macrophages allows T cells to interact with tumor cells, a process which enhances anti-PD-1 immunotherapy. These findings illustrate the relevance of current clinical trials combining a strategy that deplete or modulate macrophages with anti-PD-1 immunotherapy.


Assuntos
Imunoterapia/métodos , Macrófagos/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Movimento Celular , Ensaios Clínicos como Assunto , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Camundongos , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Citotóxicos/fisiologia , Microambiente Tumoral
13.
Cancer Immunol Res ; 7(11): 1849-1863, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31527069

RESUMO

ß-Adrenergic receptor (ß-AR) signaling exerts protumoral effects by acting directly on tumor cells and angiogenesis. In addition, ß-AR expression on immune cells affects their ability to mount antitumor immune responses. However, how ß-AR signaling impinges antitumor immune responses is still unclear. Using a mouse model of vaccine-based immunotherapy, we showed that propranolol, a nonselective ß-blocker, strongly improved the efficacy of an antitumor STxBE7 vaccine by enhancing the frequency of CD8+ T lymphocytes infiltrating the tumor (TIL). However, propranolol had no effect on the reactivity of CD8+ TILs, a result further strengthened by ex vivo experiments showing that these cells were insensitive to adrenaline- or noradrenaline-induced AR signaling. In contrast, naïve CD8+ T-cell activation was strongly inhibited by ß-AR signaling, and the beneficial effect of propranolol mainly occurred during CD8+ T-cell priming in the tumor-draining lymph node. We also demonstrated that the differential sensitivity of naïve CD8+ T cells and CD8+ TILs to ß-AR signaling was linked to a strong downregulation of ß2-AR expression related to their activation status, since in vitro-activated CD8+ T cells behaved similarly to CD8+ TILs. These results revealed that ß-AR signaling suppresses the initial priming phase of antitumor CD8+ T-cell responses, providing a rationale to use clinically available ß-blockers in patients to improve cancer immunotherapies.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Vacinas Anticâncer/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Antagonistas Adrenérgicos beta/uso terapêutico , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/uso terapêutico , Células Cultivadas , Imunoterapia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Propranolol/farmacologia , Receptores Adrenérgicos beta/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Cancer Immunol Res ; 7(12): 1958-1969, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31611243

RESUMO

Trifluridine/tipiracil (FTD/TPI) is a new antimetabolite agent used to treat chemorefractory metastatic colorectal cancer. FTD/TPI induced immunogenic cell death (ICD) in vitro in the microsatellite-stable (MSS) CT26 mouse colon carcinoma cell line, as well as in various human MSS colorectal cancer cell lines (SW620, Caco-2, and Colo-320). The combination of FTD/TPI with oxaliplatin synergized to promote ICD. In vivo, the combination was able to induce ICD, but not the single agents, although all treatment groups showed T-cell dependency. In addition, FTD/TPI and oxaliplatin did not affect regulatory T cells or myeloid-derived suppressor cells but eliminated type-2 tumor-associated macrophages (TAM2), resulting in higher cytotoxic CD8+ T-cell infiltration and activation. This effect was concomitantly associated with PD-L1 expression on tumor cells and PD-1 induction on CD8+ T cells, leading to secondary T-cell exhaustion. Finally, although anti-PD-1 was unable to synergize with FTD/TPI or oxaliplatin monotherapy, concomitant administration of anti-PD-1 to FTD/TPI and oxaliplatin enhanced the antitumor efficacy of the double chemotherapy. Our study showed a novel immunomodulatory role of FTD/TPI and oxaliplatin in depleting TAM2. The combination of oxaliplatin and FTD/TPI induced ICD in vivo, providing a rationale for the use of these drugs to eliminate immunosuppressive cells and boost checkpoint efficacy in patients with metastatic colorectal cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Oxaliplatina/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Pirrolidinas/uso terapêutico , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/imunologia , Combinação de Medicamentos , Feminino , Humanos , Morte Celular Imunogênica/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oxaliplatina/farmacologia , Pirrolidinas/farmacologia , Timina , Trifluridina/farmacologia , Uracila/farmacologia , Uracila/uso terapêutico
15.
Immunobiology ; 212(9-10): 795-812, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18086380

RESUMO

A heterogeneous set of cells that are commonly grouped as "myeloid cells", interacts in a complex landscape of physiological and pathological situations. In this review we attempt to trace a profile of the "myeloid connection" through different normal and pathological states, by analyzing common metabolic pathways of the amino acid l-arginine. Myeloid cells exert various, often divergent, actions on the immune response through mechanisms that exploit mediators of this peculiar metabolic pathway, ranging from l-arginine itself to its downstream metabolites, like nitric oxide and polyamines. Various pathological situations, including neoplastic and autoimmune diseases, as well as injury repair and infections are discussed here, showing how l-arginine metabolism is able to play a dual role, both as an active protector and a possible threat to the organism.


Assuntos
Arginina/metabolismo , Imunidade , Células Mieloides/metabolismo , Animais , Arginase/metabolismo , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Imunidade Ativa , Imunidade Inata , Infecções/imunologia , Infecções/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Células Mieloides/imunologia , Neoplasias/imunologia , Neoplasias/metabolismo , Óxido Nítrico Sintase/metabolismo , Cicatrização
16.
J Vis Exp ; (130)2017 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-29364247

RESUMO

CD8 T cell are key players in the fight against cancer. In order for CD8 T cells to kill tumor cells they need to enter into the tumor, migrate within the tumor microenvironment and respond adequately to tumor antigens. The recent development of improved imaging approaches, such as 2-photon microscopy, and the use of powerful mouse tumor models have shed light on some of the mechanisms that regulate anti-tumor T cell activities. Whereas such systems have provided valuable insights, they do not always predict human responses. In human, our knowledge in the field mainly comes from a description of fixed tumor samples from human patients, as well as in vitro studies. However, in vitro models lack the complex three-dimensional tumor milieu and, therefore, are incomplete approximations of in vivo T cell activities. Fresh slices made from explanted tissue represent a complex multi-cellular tumor environment that can act as an important link between co-cultured studies and animal models. Originally set up in murine lymph nodes1 and previously described in a JoVE article2, this approach has now been transposed to human tumors to examine the dynamics of both plated3 as well as resident T cells4. Here, a protocol for the preparation of human lung tumor slices, immunostaining of resident CD8 T and tumor cells, and tracking of CD8 T lymphocytes within the tumor microenvironment using confocal microscopy is described. This system is uniquely placed to screen for novel immunotherapy agents favoring T cell migration in tumors.


Assuntos
Linfócitos T CD8-Positivos/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Microscopia Confocal/métodos , Linfócitos T CD8-Positivos/imunologia , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia
17.
Oncoimmunology ; 6(10): e1346765, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29123960

RESUMO

Regressing tumors are usually associated with a large immune infiltrate, but the molecular and cellular interactions that govern a successful anti-tumor immunity remain elusive. Here, we have triggered type I Interferon (IFN) signaling in a breast tumor model (MMTV-PyMT) using 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a ligand of the STimulator of Interferon Genes, STING. The 2 main events rapidly triggered by DMXAA in transplanted PyMT tumors are 1) the disruption of the tumor vasculature, followed by hypoxia and cell death; 2) the release of chemokines. Both events converged to trigger the recruitment of 2 waves of immune cells: a swift, massive recruitment of neutrophils, followed by a delayed rise in monocytes and CD8 T cells in the tumor mass. Depletion experiments in vivo revealed that myeloid cell subsets and T cells need to cooperate to achieve full-blown recruitment and activation at the tumor site and to induce effective secondary cell death leading to tumor regression (Illustration 1). Altogether, our study highlights that the tumor regression induced by the STING agonist DMXAA results from a cascade of events, with an initial vessel destruction followed by several infiltration waves of immune cells which have to cooperate to amplify and sustain the initial effect. We thus provide the first global and detailed kinetic analysis of the anti-tumoral effect of DMXAA and of its different articulated steps.

19.
Front Immunol ; 6: 500, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26528284

RESUMO

T cells play a key role in the battle against cancer. To perform their antitumor activities, T cells need to adequately respond to tumor antigens by establishing contacts with either malignant cells or antigen-presenting cells. These latter functions rely on a series of migratory steps that go from entry of T cells into the tumor followed by their locomotion in the tumor stroma. Our knowledge of how T cells migrate within tumors mainly comes from experiments performed in mouse models. Whereas such systems have greatly advanced our understanding, they do not always faithfully recapitulate the disease observed in cancer patients. We previously described a technique based on tissue slices that enables to track with real-time imaging microscopy the motile behavior of fluorescent T cells plated onto fresh sections of human lung tumors. We have now refined this approach to monitor the locomotion of resident tumor-infiltrating CD8 T cells labeled with fluorescently coupled antibodies. Using this approach, our findings reveal that CD8 T cells accumulate in the stroma of ovarian and lung carcinomas but move slowly in this compartment. Conversely, even though less populated, tumors islets were found to be zones of faster migration for resident CD8 T cells. We also confirm the key role played by collagen fibers, which, by their orientation, spacing and density, control the distribution and migration of resident CD8 T cells within the tumor stroma. We have subsequently demonstrated that, under some physical tissue constraints, CD8 T cells exhibited a mode of migration characterized by alternate forward and backward movements. In sum, using an ex vivo assay to track CD8 T cells in fresh human tumor tissues, we have identified the extracellular matrix as a major stromal component in influencing T cell migration, thereby impacting the control of tumor growth. This approach will aid in the development and testing of novel immunotherapy strategies to promote T cell migration in tumors.

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