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1.
Oncoimmunology ; 8(11): e1657375, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31646107

RESUMO

We have recently shown that chemotherapy with immunogenic cell death (ICD)-inducing agents can be advantageously combined with fasting regimens or caloric restriction mimetics (CRMs) to achieve superior tumor growth control via a T cell-dependent mechanism. Here, we show that the blockade of the CD11b-dependent extravasation of myeloid cells blocks such a combination effect as well. Based on the characterization of the myeloid and lymphoid immune infiltrates, including the expression pattern of immune checkpoint proteins (and noting a chemotherapy-induced overexpression of programmed death-ligand 1, PD-L1, on both cancer cells and leukocytes, as well as a reduced frequency of exhausted CD8+ T cells positive for programmed cell death 1 protein, PD-1), we then evaluated the possibility to combine ICD inducers, CRMs and targeting of the PD-1/PD-L1 interaction. While fasting or CRMs failed to improve tumor growth control by PD-1 blockade, ICD inducers alone achieved a partial sensitization to treatment with a PD-1-specific antibody. However, definitive cure of most of the tumor-bearing mice was only achieved by a tritherapy combining (i) ICD inducers exemplified by mitoxantrone and oxaliplatin, (ii) CRMs exemplified by hydroxycitrate and spermidine and substitutable for by fasting, and (iii) immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 interaction. Altogether, these results point to the possibility of synergistic interactions among distinct classes of anticancer agents.

2.
Autophagy ; 12(10): 1962-1964, 2016 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-27532519

RESUMO

Cancer can be viewed in 2 rather distinct ways, namely (i) as a cell-autonomous disease in which malignant cells have escaped control from cell-intrinsic barriers against proliferation and dissemination or (ii) as a systemic disease that involves failing immune control of aberrant cells. Since macroautophagy/autophagy generally increases the fitness of cells as well as their resistance against endogenous or iatrogenic (i.e., relating to illness due to medical intervention) stress, it has been widely proposed that inhibition of autophagy would constitute a valid strategy for sensitizing cancer cells to chemotherapy or radiotherapy. Colliding with this cell-autonomous vision, however, we found that immunosurveillance against transplantable, carcinogen-induced or genetically engineered cancers can be improved by pharmacologically inducing autophagy with caloric restriction mimetics. This positive effect depends on autophagy induction in cancer cells and is mediated by alterations in extracellular ATP metabolism, namely increased release of immunostimulatory ATP and reduced adenosine-dependent recruitment of immunosuppressive regulatory T cells into the tumor bed. The combination of autophagy inducers and chemotherapeutic agents is particularly efficient in reducing cancer growth through the stimulation of CD8+ T lymphocyte-dependent anticancer immune responses.


Assuntos
Autofagia , Neoplasias/patologia , Neoplasias/terapia , Trifosfato de Adenosina/metabolismo , Animais , Humanos , Vigilância Imunológica , Camundongos , Neoplasias/imunologia
3.
Cancer Cell ; 30(1): 147-160, 2016 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-27411589

RESUMO

Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed.


Assuntos
Citratos/administração & dosagem , Neoplasias Experimentais/dietoterapia , Neoplasias Experimentais/tratamento farmacológico , Espermidina/administração & dosagem , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Autofagia , Proteína 5 Relacionada à Autofagia/genética , Restrição Calórica/métodos , Linhagem Celular Tumoral , Citratos/farmacologia , Humanos , Metotrexato/administração & dosagem , Metotrexato/farmacologia , Camundongos , Monitorização Imunológica , Mutação , Transplante de Neoplasias , Neoplasias Experimentais/imunologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Espermidina/farmacologia
4.
Oncoimmunology ; 5(6): e1139275, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27471610

RESUMO

The loss-of-function mutation of formyl peptide receptor 1 (FPR1) has a negative impact on the progression-free and overall survival of breast cancer patients treated with anthracycline-based adjuvant chemotherapy. This effect may be attributed to the fact that chemotherapy-induced antitumor immunity requires FPR1 and that such anticancer immune responses are responsible for the long-term effects of chemotherapy. Here, we investigated the possible contribution of FPR1 to the efficacy of a combination of mitoxantrone (MTX) and cyclophosphamide (CTX) for the treatment of hormone-induced breast cancer. Breast cancer induced by a combination of medroxyprogesterone acetate (MPA) and 7,12-Dimethylbenz[a]anthracene (DMBA) could be successfully treated with MTX plus CTX in thus far that tumor growth was retarded and overall survival was extended (as compared to vehicle-only treated controls). However, the therapeutic efficacy of the combination therapy was completely abolished when FPR1 receptors were blocked by means of cyclosporin H (CsH). Future genetic studies on neoadjuvant chemotherapy-treated breast cancers are warranted to validate these findings at the clinical level.

5.
Oncoimmunology ; 5(5): e1118600, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27467929

RESUMO

Several pattern recognition receptors including toll-like receptors and purinergic receptors are implicated in the anticancer immune response elicited by anthracyclines or oxaliplatin. Recently, formyl peptide receptor-1 (FPR1) has been involved in this response as well. FPR1 is required for the correct positioning of dendritic cells (DC) close to dying cancer cells. A genetic defect in FPR1 abrogates cross-presentation of tumor antigens by DC, thereby compromising therapy-elicited immunosurveillance.

6.
Science ; 350(6263): 972-8, 2015 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-26516201

RESUMO

Antitumor immunity driven by intratumoral dendritic cells contributes to the efficacy of anthracycline-based chemotherapy in cancer. We identified a loss-of-function allele of the gene coding for formyl peptide receptor 1 (FPR1) that was associated with poor metastasis-free and overall survival in breast and colorectal cancer patients receiving adjuvant chemotherapy. The therapeutic effects of anthracyclines were abrogated in tumor-bearing Fpr1(-/-) mice due to impaired antitumor immunity. Fpr1-deficient dendritic cells failed to approach dying cancer cells and, as a result, could not elicit antitumor T cell immunity. Experiments performed in a microfluidic device confirmed that FPR1 and its ligand, annexin-1, promoted stable interactions between dying cancer cells and human or murine leukocytes. Altogether, these results highlight the importance of FPR1 in chemotherapy-induced anticancer immune responses.


Assuntos
Antraciclinas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Receptores de Formil Peptídeo/fisiologia , Alelos , Animais , Anexina A1/metabolismo , Anexina A1/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Humanos , Imunidade Inata/genética , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Camundongos , Polimorfismo de Nucleotídeo Único , Receptores de Formil Peptídeo/genética , Linfócitos T/imunologia
7.
Nat Med ; 20(11): 1301-9, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25344738

RESUMO

Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell-mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN-α and IFN-ß receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN-related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such 'viral mimicry' constitutes a hallmark of successful chemotherapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Doxorrubicina/uso terapêutico , Interferon Tipo I/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Antraciclinas/farmacologia , Antraciclinas/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Quimiocina CXCL10/metabolismo , Doxorrubicina/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunocompetência/efeitos dos fármacos , Interferon Tipo I/biossíntese , Camundongos Endogâmicos C57BL , Proteínas de Resistência a Myxovirus/metabolismo , Terapia Neoadjuvante , Metástase Neoplásica , RNA/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor de Interferon alfa e beta/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 3 Toll-Like/metabolismo , Resultado do Tratamento
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