RESUMO
Tumors poorly infiltrated by T cells are more resistant to immunogenic chemotherapies and checkpoint inhibition than highly infiltrated tumors. Using murine models, we found that CCR6+ type 3 innate lymphoid cells (ILC3s) can trigger an increase in the number of T cells infiltrating a tumor. Shortly after administration of cisplatin chemotherapy, production of the chemokine CCL20 and proinflammatory cytokine IL-1ß at the tumor site led to the recruitment and activation of ILC3s. Within the tumor, ILC3 production of the chemokine CXCL10 was responsible for the recruitment of CD4+ and CD8+ T lymphocytes to the tumor. ILC3-dependent infiltration of T cells was essential for antitumor immune responses and increased the efficacy of checkpoint inhibition. Thus, we reveal an essential role of CCL20 and IL-1ß, which promote ILC3-dependent antitumor immunity and enhance tumor sensitivity to immunotherapy.
Assuntos
Imunidade Inata/imunologia , Linfócitos/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Citocinas/imunologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
During tumor growth, angiogenesis is required to ensure oxygen and nutrient transport to the tumor. Vascular endothelial growth factor (VEGF) is the major inducer of angiogenesis and appears to be a key modulator of the anti-tumor immune response. Indeed, VEGF modulates innate and adaptive immune responses through direct interactions and indirectly by modulating protein expressions on endothelial cells or vascular permeability. The inhibition of the VEGF signaling pathway is clinically approved for the treatment of several cancers. Therapies targeting VEGF can modulate the tumor vasculature and the immune response. In this review, we discuss the roles of VEGF in the anti-tumor immune response. In addition, we summarize therapeutic strategies based on its inhibition, and their clinical approval.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Fatores Imunológicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Imunidade Adaptativa/efeitos dos fármacos , Anticorpos Monoclonais Humanizados/uso terapêutico , Bevacizumab/uso terapêutico , Permeabilidade Capilar/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Células Endoteliais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade Inata/efeitos dos fármacos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Neovascularização Patológica/patologia , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Transdução de Sinais , Sorafenibe/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/imunologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/imunologia , RamucirumabRESUMO
During carcinogenesis, tumors set various mechanisms to help support their development. Angiogenesis is a crucial process for cancer development as it drives the creation of blood vessels within the tumor. These newly formed blood vessels insure the supply of oxygen and nutrients to the tumor, helping its growth. The main factors that regulate angiogenesis are the five members of the vascular endothelial growth factor (VEGF) family. Angiogenesis is a hallmark of cancer and has been the target of new therapies this past few years. However, angiogenesis is a complex phenomenon with many redundancy pathways that ensure its maintenance. In this review, we will first describe the consecutive steps forming angiogenesis, as well as its classical regulators. We will then discuss how the cytokines and chemokines present in the tumor microenvironment can induce or block angiogenesis. Finally, we will focus on the therapeutic arsenal targeting angiogenesis in cancer and the challenges they have to overcome.