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: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
| PRJNA493023 | ENA
Project description:Heterogeneous Tumor Microenvironment of Non-Small Cell Lung Cancer
Project description:Immune responses against tumor cells depend on T lymphocyte attraction and activity within the tumor microenvironment. Specialized immune-interacting fibroblasts, commonly referred to as fibroblastic reticular cells (FRC), form specialized niches in secondary lymphoid organs, originate from embryonic progenitors and foster T cell activation. FRCs have also been detected in tertiary lymphoid structures (TLS) in tumors, differentiating from cancer associated fibroblasts. However, the identity and differentiation of niche-forming cells that foster intra-tumoral T cell activity have remained elusive. Here, we employed single cell RNA-sequencing of EYFP+ fibroblasts and GP33/34-Tetramer+CD8+ T cells from experimental murine lung cancer and cell fate-mapping analysis, which revealed the ability of FRC subsets in lung tumors to differentiate from progenitors situated in mural and adventitial sites. Ablation of FRC progenitors in Tumor T cell environments (TTEs) of murine lungs led to reduced anti-tumor T cell activity and loss of tumor control during experimental coronavirus vector-based immunotherapy. Collectively, our study defines lung cancer-associated FRC niches and key processes involved in stromal-T cell interaction that could pave the way for improved cancer immunotherapy.
