Project description:Metastatic breast cancer is the overwhelming cause of breast cancer mortality and is still incurable. Development of immunotherapy is an exciting new area of research in metastatic breast cancer; however, the extreme immunosuppressive tumor environment poses a major challenge. Here we provide evidence that a particular isoform of Ron kinase, short-form Ron (SF-Ron), strongly suppresses anti-tumor immune responses and promotes metastatic outgrowth of mammary tumors. We used single-cell RNA-sequencing to identify the CD45+ immune cell populations within the common site of breast cancer metastasis, lung, from either wild-type (WT) or SF-Ron knockout (Ron SF-/-) in the MMTV-PyMT experimental metastasis model. SF-Ron was required for breast cancer metastasis develoment and the skewing of the lung immune microenvironment toward the immune-suppressive pro-tumor microenvironment. Lack of SF-Ron not only enhanced tumor-specific immune response, but also led to accumulation of less differentiated TCF1+ CD4+ T cells in the metastatic lungs that were endowed with type I helper T cell-like (Th1-like) differentiation potential. Mice treated with a small molecule Ron kinase inhibitor produced significantly more tumor-specific CD8+ T cells and reduced metastatic outgrowth. Our study indicates that blocking Ron, specifically SF-Ron, remodels the metastatic lung microenvironment to enhance anti-tumor immunity and clear metastatic lesions, providing strong pre-clinical evidence for Ron kinase inhibitors to augment immunotherapy for treatment of metastatic breast cancer.
Project description:<p>Small cell lung cancer (SCLC) exhibits profound immunometabolic suppression that impairs antigen presentation and constrains immunotherapy efficacy. Through integrated multi-omics analyses of primary human SCLC tumors, we identified midkine (MDK) as a dominant tumor-secreted driver of immune evasion. Mechanistically, MDK activates STAT3 to induce indoleamine 2,3-dioxygenase 1 (IDO1), driving tryptophan-kynurenine metabolic reprogramming. This axis suppresses myeloid antigen presentation, reduces HLA class I expression, and impairs CD8+ T cell function, establishing a immunosuppressive tumor microenvironment (TME). We engineered DLL3-targeted CAR T cells secreting anti-MDK scFv. These dual-functional CAR T cells neutralize MDK within the TME, restore antigen presentation, alleviate metabolic suppression, and reinvigorate CD8+ T cell responses. In SCLC models, they exhibited markedly enhanced antitumor activity, improved metabolic fitness, and durable immune activation without systemic toxicity. Collectively, our findings identify MDK as a key immunometabolic regulator and support sMDK-DLL3 CAR T cells as a targeted immunotherapy for SCLC.</p>
Project description:Despite substantial progress in lung cancer immunotherapy, the overall response rate in KRAS-mutant lung adenocarcinoma (ADC) patients remains low. Combining standard immunotherapy with adjuvant approaches that enhance adaptive immune responses—such as epigenetic modulation of anti-tumor immunity—is therefore an attractive strategy. To identify epigenetic regulators of tumor immunity, we constructed an epigenetic-focused sgRNA library, and performed an in vivo CRISPR screen in KrasG12D/P53-/- (KP) lung ADC model. Our data showed that loss of the histone chaperone Asf1a in tumor cells sensitizes tumors to anti-PD-1 treatment. Mechanistic studies revealed that tumor cell intrinsic Asf1a deficiency induced immunogenic macrophage differentiation in the tumor microenvironment by upregulating GM-CSF expression and potentiated T cell activation in combination with anti-PD-1. Our results provide a rationale for a novel combination therapy consisting of Asf1a inhibition and anti-PD-1 immunotherapy.
2019-11-26 | GSE138571 | GEO
Project description:Heterogeneous Tumor Microenvironment of Non-Small Cell Lung Cancer
| PRJNA490786 | ENA
Project description:Heterogeneous Tumor Microenvironment of Non-Small Cell Lung Cancer
| PRJNA506151 | ENA
Project description:Heterogeneous Tumor Microenvironment of Non-Small Cell Lung Cancer
