免疫检查点剖析.ppt

* Immune checkpoint blockade: Releasing the brake towards hematological malignancies 2016.9.1 1、Introduction 2、Biology of immune checkpoints 3、Checkpoints deregulation in hematological malignancies 4、Clinical impact of drugs blocking immune checkpoints in hematological malignancies 5、Opportunities for combination approaches 6、Conclusions Contents Introduction Malignant cells provide neoantigens generated by vast tumor- specific mutation as potential targets for immune destruction by host immunosurveillance. Checkpoints are a specific subset of negative regulators that normally deliver inhibitory signals to limit effector T cell response and maintain self-tolerance during anti-microbial immune responses. Malignant cells are able to co-opt immune checkpoint molecules to avoid immune recognition and elimination. The ability of checkpoint blockade to restore both innate and adaptive antitumor immunity makes them ideal candidates for cancer treatment. So far, checkpoint blockade antibodies against cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) have been approved by the United States Food and Drug Administration for the treatment of advanced melanoma. Hematological malignancies are often accompanied by immune dysregulation. Therefore, the immune restoration through check-point blockade may benefit patients with hematological malignancies. Biology of immune checkpoints The CD28-CTLA4 axis 2.The PD-1 signaling pathway Checkpoints deregulation in hematological malignancies Most patients with acute myeloid leukemia (AML), chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia (CLL) express CTLA-4 on the cell surface and in the cytoplasm. In contrast, CTLA-4 expression in acute T-lymphocytic leukemia (T-ALL) and acute B-lymphocytic leukemia (T-BLL) is mostly cytoplasmic. Our knowledge regarding the role of CTLA-4 in hematologic malignancies is limited. The CTLA4 CT60 AA genotype has been associated wi