RESUMO
PURPOSE: Acquired hematopoietic failure is commonly caused by therapeutic and accidental exposure of the bone marrow (BM) to toxic agents. Efficient recovery from BM failure is dictated not only by the intrinsic sensitivity and proliferation capacity of the hematopoietic stem and progenitor cells but also by the BM environment niche. Identification of genetic factors that improve recovery from hematopoietic failure is essential. Vertebrate SETD4 is a poorly characterized and putatively nonhistone methyltransferase. This study aims to identify the roles of SETD4 in BM recovery. METHODS AND MATERIALS: An inducible SETD4 knockout mouse model (Setd4flox/flox;Rosa26-CreERT2+) was used. Adult sex-matched littermates were treated with tamoxifen to induce Setd4 deletion or oil as the control. Tamoxifen-treated Setd4wt/wt;Rosa26-CreERT2+ mice were included as another control. Those mice were irradiated to induce hematopoietic syndrome and analyzed to identify the roles and mechanisms of Setd4 in of BM recovery. RESULTS: Loss of Setd4 in adult mice improved the survival of whole-body irradiation-induced BM failure. This was associated with improved recoveries of long-term and short-term hematopoietic stem cells (HSCs) and early progenitor cells. BM transplantation analyses surprisingly showed that the improved recovery was not due to radiation resistance of the Setd4-deficient HSCs but that Setd4-deficient HSCs were actually more sensitive to radiation. However, the Setd4-deficient mice were better recipients for allogeneic HSC transplantation. Furthermore, there was enhanced splenic erythropoiesis in Setd4-deficient mice. CONCLUSION: These findings not only revealed a previously unrecognized role of Setd4 as a unique modulator of hematopoiesis but also underscored the critical role of the BM niche in recovery from hematopoietic failure. Our study also implicated Setd4 as a potential target for therapeutic inhibition to improve the conditioning of the BM niche before allogeneic transplantation.
Assuntos
Hematopoese/genética , Hematopoese/efeitos da radiação , Metiltransferases/deficiência , Metiltransferases/genética , Animais , Transplante de Medula Óssea , Técnicas de Inativação de Genes , Camundongos , Irradiação Corporal Total/efeitos adversosRESUMO
The molecular mechanisms leading to resistance to PD-1 blockade are largely unknown. Here, we characterize tumor biopsies from a patient with melanoma who displayed heterogeneous responses to anti-PD-1 therapy. We observe that a resistant tumor exhibited a loss-of-function mutation in the tumor suppressor gene FBXW7, whereas a sensitive tumor from the same patient did not. Consistent with a functional role in immunotherapy response, inactivation of Fbxw7 in murine tumor cell lines caused resistance to anti-PD-1 in immunocompetent animals. Loss of Fbxw7 was associated with altered immune microenvironment, decreased tumor-intrinsic expression of the double-stranded RNA (dsRNA) sensors MDA5 and RIG1, and diminished induction of type I IFN and MHC-I expression. In contrast, restoration of dsRNA sensing in Fbxw7-deficient cells was sufficient to sensitize them to anti-PD-1. Our results thus establish a new role for the commonly inactivated tumor suppressor FBXW7 in viral sensing and sensitivity to immunotherapy. SIGNIFICANCE: Our findings establish a role of the commonly inactivated tumor suppressor FBXW7 as a genomic driver of response to anti-PD-1 therapy. Fbxw7 loss promotes resistance to anti-PD-1 through the downregulation of viral sensing pathways, suggesting that therapeutic reactivation of these pathways could improve clinical responses to checkpoint inhibitors in genomically defined cancer patient populations.This article is highlighted in the In This Issue feature, p. 1241.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Proteína 7 com Repetições F-Box-WD/genética , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Linhagem Celular Tumoral/transplante , Proteína DEAD-box 58/genética , Proteína DEAD-box 58/metabolismo , Modelos Animais de Doenças , Proteína 7 com Repetições F-Box-WD/metabolismo , Regulação Neoplásica da Expressão Gênica/imunologia , Células HeLa , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Helicase IFIH1 Induzida por Interferon/genética , Helicase IFIH1 Induzida por Interferon/metabolismo , Mutação com Perda de Função , Masculino , Camundongos , Mutagênese Sítio-Dirigida , Receptor de Morte Celular Programada 1/antagonistas & inibidores , RNA de Cadeia Dupla/imunologia , RNA de Cadeia Dupla/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
In the initially published version of this article online in advance of print, a reference (Ajina, A. & Maher, J. Prospects for combined use of oncolytic viruses and CAR T-cells. J. Immunother. Cancer 5, 90 (2017)) was omitted in error from the following sentence: "The ability of oncolytic viruses to increase the expression of MHC class I molecules by cancer cells is also predicted to enhance ACT with TILs or TCR-engineered and chimeric antigen receptor (CAR) T cells that target tumour-specific antigens". This has been corrected in the HTML and PDF versions of the manuscript.
RESUMO
Oncolytic viruses can be usefully integrated into tumour immunotherapies, as they target multiple steps within the cancer-immunity cycle. Oncolytic viruses directly lyse tumour cells, leading to the release of soluble antigens, danger signals and type I interferons, which drive antitumour immunity. In addition, some oncolytic viruses can be engineered to express therapeutic genes or can functionally alter tumour-associated endothelial cells, further enhancing T cell recruitment into immune-excluded or immune-deserted tumour microenvironments. Oncolytic viruses can also utilize established tumours as an in situ source of neoantigen vaccination through cross-presentation, resulting in regression of distant, uninfected tumours. These features make oncolytic viruses attractive agents for combination strategies to optimize cancer immunotherapy.