Project description:Solid tumours evade immunosurveillance through a plethora of mechanisms. It remains elusive how the development and functions of B cells vary in different tumour contexts. Here, we observed distinct patterns of B cell abnormality in triple-negative breast cancer and termed these patterns “tumour-induced B cell abnormality” type (TiBA). TiBA results from disrupted early B cell development in the bone marrow, which is associated with abnormal myelopoiesis. This study highlights the heterogeneity of tumour-induced systemic changes on B cells and lays foundation for the precision treatment of patients with different B cell abnormalities.
Project description:Solid tumours evade immunosurveillance through a plethora of mechanisms. It remains elusive how the development and functions of B cells vary in different tumour contexts. Here, we observed distinct patterns of B cell abnormality in triple-negative breast cancer and termed these patterns “tumour-induced B cell abnormality” type (TiBA). TiBA results from disrupted early B cell development in the bone marrow, which is associated with abnormal myelopoiesis. This study highlights the heterogeneity of tumour-induced systemic changes on B cells and lays foundation for the precision treatment of patients with different B cell abnormalities.
Project description:Hysteresis, a ubiquitous phenomenon in nonlinear systems, plays a vital role in diverse scientific disciplines. Here, we demonstrated the presence of hysteresis in the expression of interleukin-10 receptor (IL-10R) within the tumour microenvironment (TME) during bacterial immunotherapy. The engineered Salmonella enterica, administered intravenously, exhibited remarkable efficacy in multiple tumour types, effectively eliminating tumours and preventing recurrence and metastasis. We found that the hysteretic response of IL-10R can prime TME for bacterial homing and reinvigorate intratumoural CD8+ T cells. Furthermore, the differential IL-10R levels observed in different human tumour types suggest a potential correlation with clinical outcomes. Overall, our study not only uncovers the central role of hysteresis in driving the therapeutic effects of bacterial immunotherapy, but also provides a framework for intratumoural immunomodulation in solid tumour treatment.
Project description:Gene expression quantification of PanCancer IO genes from paired tumour biopsies from 24 patients with pan-cancer solid tumours, before and after treatment with MTL-CEBPA and pembrolizumab.
Project description:Cytotherapy is a revolutionary therapeutic agent representing the forefront of current cancer therapy, but its poor efficacy in the treatment of solid tumours remains challenging. Integration of tumour infiltration, targeted elimination and tumour microenvironment (TME) regulation functions in designing effective cytopharmaceuticals for solid tumours is necessary. Here, we designed on-demand editing macrophages (RILO-M1-G) constructed by surface glypican-3 (GPC3) peptide anchoring and inner R848/INCB024360-lipid particle (RILO) packing to combat hepatocellular carcinoma (HCC). Based on the tumour tendency and deep penetration of macrophages, the anchored GPC3 peptide on the membrane surface promoted macrophage-tumour cell recognition, thus enhancing specific tumour targeting and phagocytosis of tumour cells with high GPC3 expression. The packed RILOs were wrapped by C16-ceramide fused Escherichia coli-originated outer membrane vesicles (OMVs). OMVs facilitated RILO internalization through caveolin-mediated endocytosis to maintain a suitable nanostructure, C16-ceramide induced membrane invagination and exosome generation, leading to the release of packed RILOs through exosomes. These exosomes containing the TLR7/8 agonist R848 and IDO1 inhibitor INCB024360 enabled remodelling of the immunosuppressive TME by regulating the tumour-associated macrophage phenotype and enhancing T-cell viability. Furthermore, treatments with RILO-M1-G exerted remarkable therapeutic efficacy in a H22 tumour-bearing mouse model, rechallenged tumour model and orthotopic HCC mouse model compared with that of first-line HCC therapy. Overall, RILO-M1-G offered a new cytotherapeutic strategy for meeting the clinical demands of solid tumour treatment.
Project description:The contribution of the majority of frequently mutated genes to tumourigenesis is not fully defined. Many aggressive human cancers, such as triple negative breast cancers (TNBCs), have a poor prognosis and lack tractable biomarkers and targeted therapeutic options. Here, we systematically characterize loss-of-function mutations to generate a functional map of novel driver genes in a 3-dimensional model of breast cancer heterogeneity that more readily recapitulates the unfavourable tumour microenvironment in vivo. This identified the histone acetyltransferase CREBBP as a potent tumour suppressor gene whose silencing provided a 3D-specific growth advantage only under oxygen and nutrient deplete conditions. CREBBP protein expression was altered in a substantial proportion of TNBCs as well as several other solid tumours, including endometrial, bladder, ovarian and squamous lung cancers. In multiple primary tumours and cell models, loss of CREBBP activity resulted in upregulation of the FOXM1 transcriptional network. Strikingly, treatment with a range of CDK4/6 inhibitors (CDK4/6i), that indirectly target FOXM1 activity, selectively impaired growth in both CREBBP-altered spheroids and cell line xenografts and patient derived models from multiple tumour types. This study is the first to provide rationale for CREBBP as a biomarker for CDK4/6i response in cancer representing a new treatment paradigm for tumours that harbour CREBBP alterations that have limited therapeutic options.
Project description:Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer. We found that targeted therapy with BRAF, ALK, or EGFR inhibitors induces a complex network of secreted signals in drug-stressed melanoma and lung adenocarcinoma cells. This therapy-induced secretome (TIS) stimulates the outgrowth, infiltration and metastasis of drug-resistant cancer clones in the tumour. Additionally, the TIS supports the survival of drug-sensitive cells, contributing to incomplete tumour regression. We used transcriptomic analysis of sensitive tumour cells and xenograft tumours treated with vehicle, vemurafenib, or crizotinib to identify the transcriptional drivers and to dissect the TIS in melanoma (A375, Colo800, UACC62) and lung adenocarcinoma (H3122). In addition, we utilize cell type–specific mRNA purification by translating ribosome affinity purification (TRAP) to identify pathways that are up-regulated in resistant cells (A375R) in response to the regressing tumour microenvironment.
Project description:Pericytes are integral components of the tissue vasculature and have essential functions in tumour angiogenesis. Endosialin (CD248) is a type I transmembrane glycoprotein highly expressed on pericytes in the tumour vasculature of most solid tumours, however it is low or negligibly expressed on normal tissue pericytes. Experiments using wild-type and endosialin-knockout mice has revealed that stromal endosialin expression facilitates intravasation of tumor cells from the primary tumor into the circulation, thereby promoting metastatic dissemination.