Project description:Immunotherapy is becoming a mainstay in the treatment of NSCLC. We profiled immune cells of 35 early stage NSCLC lesions using multiscale single cell sequencing, including scRNAseq, CITEseq, and TCRseq.
Project description:To shed light on the complexity of tumor-infiltrating immune cells in non-small cell lung cancer (NSCLC) patients and triple negative breast cancer (TNBC) patients with a metastatic brain tumor, we performed massively-parallel single-cell RNA sequencing on 12,196 cells,including 2,012 myeloid cells from 3 surgically removed brain lesions of treatment-naïve NSCLC patients, as well as 6,000 cells from brain lesion of one triple negative breast cancer patient. We found a lack of T lymphocyte infiltration and activation, as well as the vast expansion of tumor-associated macrophage (TAM) in the brain lesions of NSCLC and breast cancer patients. We identified a unique alternative activation (M2) gene expression pattern of the TAM in the brain metastasis and a lack of known T cell co-stimulator expression. Accumulation of M2 polarized TAM may, therefore, cause the comprised anti-tumor T cell response in metastatic brain lesions.
Project description:To explore the diversity of the MF compartment in human non-small cell lung carcinoma lesions (NSCLC), we first performed an unbiased single cell RNA-sequencing (scRNAseq) analysis of CD45+ tumor-associated leukocytes. We identified distinct MF populations enriched in human tumors and found related MF phenotypes in mouse lung tumors. Using lineage-tracing, we discovered these discrete MF populations differ in origin and have a distinct temporal and spatial distribution in the TME. Longitudinal tumor imaging revealed that upon tumor cell seeding, TRMF accumulate in proximity to tumor cells to promote tumor cell epithelial mesenchymal transition and invasiveness, while also inducing a potent T regulatory (Treg) response that protects tumor cells from adaptive immunity. TRMF depletion prior to tumor implantation, while sparing Mo-MF, did not affect tumor cell seeding but significantly reduced Treg numbers, dampened the Treg regulatory program, promoted the accumulation of CD8+ T cells in tumor lesions, and reduced tumor invasiveness and growth. During tumor growth, TRMF redistributed at the periphery of the TME, which becomes dominated by Mo-MF both in mouse and human NSCLC lesions, and TRMF depletion in later stage tumors, had little effect on tumor growth. This study identifies the distinct contribution of the TRMF lineage to early lung cancer invasiveness and establish TRMF as a potential novel target to treat early lung cancer lesions.
Project description:To explore the diversity of the MF compartment in human non-small cell lung carcinoma lesions (NSCLC), we first performed an unbiased single cell RNA-sequencing (scRNAseq) analysis of CD45+ tumor-associated leukocytes. We identified distinct MF populations enriched in human tumors and found related MF phenotypes in mouse lung tumors. Using lineage-tracing, we discovered these discrete MF populations differ in origin and have a distinct temporal and spatial distribution in the TME. Longitudinal tumor imaging revealed that upon tumor cell seeding, TRMF accumulate in proximity to tumor cells to promote tumor cell epithelial mesenchymal transition and invasiveness, while also inducing a potent T regulatory (Treg) response that protects tumor cells from adaptive immunity. TRMF depletion prior to tumor implantation, while sparing Mo-MF, did not affect tumor cell seeding but significantly reduced Treg numbers, dampened the Treg regulatory program, promoted the accumulation of CD8+ T cells in tumor lesions, and reduced tumor invasiveness and growth. During tumor growth, TRMF redistributed at the periphery of the TME, which becomes dominated by Mo-MF both in mouse and human NSCLC lesions, and TRMF depletion in later stage tumors, had little effect on tumor growth. This study identifies the distinct contribution of the TRMF lineage to early lung cancer invasiveness and establish TRMF as a potential novel target to treat early lung cancer lesions.
Project description:To explore the diversity of the MF compartment in human non-small cell lung carcinoma lesions (NSCLC), we first performed an unbiased single cell RNA-sequencing (scRNAseq) analysis of CD45+ tumor-associated leukocytes. We identified distinct MF populations enriched in human tumors and found related MF phenotypes in mouse lung tumors. Using lineage-tracing, we discovered these discrete MF populations differ in origin and have a distinct temporal and spatial distribution in the TME. Longitudinal tumor imaging revealed that upon tumor cell seeding, TRMF accumulate in proximity to tumor cells to promote tumor cell epithelial mesenchymal transition and invasiveness, while also inducing a potent T regulatory (Treg) response that protects tumor cells from adaptive immunity. TRMF depletion prior to tumor implantation, while sparing Mo-MF, did not affect tumor cell seeding but significantly reduced Treg numbers, dampened the Treg regulatory program, promoted the accumulation of CD8+ T cells in tumor lesions, and reduced tumor invasiveness and growth. During tumor growth, TRMF redistributed at the periphery of the TME, which becomes dominated by Mo-MF both in mouse and human NSCLC lesions, and TRMF depletion in later stage tumors, had little effect on tumor growth. This study identifies the distinct contribution of the TRMF lineage to early lung cancer invasiveness and establish TRMF as a potential novel target to treat early lung cancer lesions.
Project description:To explore the diversity of the MF compartment in human non-small cell lung carcinoma lesions (NSCLC), we first performed an unbiased single cell RNA-sequencing (scRNAseq) analysis of CD45+ tumor-associated leukocytes. We identified distinct MF populations enriched in human tumors and found related MF phenotypes in mouse lung tumors. Using lineage-tracing, we discovered these discrete MF populations differ in origin and have a distinct temporal and spatial distribution in the TME. Longitudinal tumor imaging revealed that upon tumor cell seeding, TRMF accumulate in proximity to tumor cells to promote tumor cell epithelial mesenchymal transition and invasiveness, while also inducing a potent T regulatory (Treg) response that protects tumor cells from adaptive immunity. TRMF depletion prior to tumor implantation, while sparing Mo-MF, did not affect tumor cell seeding but significantly reduced Treg numbers, dampened the Treg regulatory program, promoted the accumulation of CD8+ T cells in tumor lesions, and reduced tumor invasiveness and growth. During tumor growth, TRMF redistributed at the periphery of the TME, which becomes dominated by Mo-MF both in mouse and human NSCLC lesions, and TRMF depletion in later stage tumors, had little effect on tumor growth. This study identifies the distinct contribution of the TRMF lineage to early lung cancer invasiveness and establish TRMF as a potential novel target to treat early lung cancer lesions.
Project description:To explore the diversity of the MF compartment in human non-small cell lung carcinoma lesions (NSCLC), we first performed an unbiased single cell RNA-sequencing (scRNAseq) analysis of CD45+ tumor-associated leukocytes. We identified distinct MF populations enriched in human tumors and found related MF phenotypes in mouse lung tumors. Using lineage-tracing, we discovered these discrete MF populations differ in origin and have a distinct temporal and spatial distribution in the TME. Longitudinal tumor imaging revealed that upon tumor cell seeding, TRMF accumulate in proximity to tumor cells to promote tumor cell epithelial mesenchymal transition and invasiveness, while also inducing a potent T regulatory (Treg) response that protects tumor cells from adaptive immunity. TRMF depletion prior to tumor implantation, while sparing Mo-MF, did not affect tumor cell seeding but significantly reduced Treg numbers, dampened the Treg regulatory program, promoted the accumulation of CD8+ T cells in tumor lesions, and reduced tumor invasiveness and growth. During tumor growth, TRMF redistributed at the periphery of the TME, which becomes dominated by Mo-MF both in mouse and human NSCLC lesions, and TRMF depletion in later stage tumors, had little effect on tumor growth. This study identifies the distinct contribution of the TRMF lineage to early lung cancer invasiveness and establish TRMF as a potential novel target to treat early lung cancer lesions.
Project description:To explore the diversity of the MF compartment in human non-small cell lung carcinoma lesions (NSCLC), we first performed an unbiased single cell RNA-sequencing (scRNAseq) analysis of CD45+ tumor-associated leukocytes. We identified distinct MF populations enriched in human tumors and found related MF phenotypes in mouse lung tumors. Using lineage-tracing, we discovered these discrete MF populations differ in origin and have a distinct temporal and spatial distribution in the TME. Longitudinal tumor imaging revealed that upon tumor cell seeding, TRMF accumulate in proximity to tumor cells to promote tumor cell epithelial mesenchymal transition and invasiveness, while also inducing a potent T regulatory (Treg) response that protects tumor cells from adaptive immunity. TRMF depletion prior to tumor implantation, while sparing Mo-MF, did not affect tumor cell seeding but significantly reduced Treg numbers, dampened the Treg regulatory program, promoted the accumulation of CD8+ T cells in tumor lesions, and reduced tumor invasiveness and growth. During tumor growth, TRMF redistributed at the periphery of the TME, which becomes dominated by Mo-MF both in mouse and human NSCLC lesions, and TRMF depletion in later stage tumors, had little effect on tumor growth. This study identifies the distinct contribution of the TRMF lineage to early lung cancer invasiveness and establish TRMF as a potential novel target to treat early lung cancer lesions.
Project description:To explore the diversity of the MF compartment in human non-small cell lung carcinoma lesions (NSCLC), we first performed an unbiased single cell RNA-sequencing (scRNAseq) analysis of CD45+ tumor-associated leukocytes. We identified distinct MF populations enriched in human tumors and found related MF phenotypes in mouse lung tumors. Using lineage-tracing, we discovered these discrete MF populations differ in origin and have a distinct temporal and spatial distribution in the TME. Longitudinal tumor imaging revealed that upon tumor cell seeding, TRMF accumulate in proximity to tumor cells to promote tumor cell epithelial mesenchymal transition and invasiveness, while also inducing a potent T regulatory (Treg) response that protects tumor cells from adaptive immunity. TRMF depletion prior to tumor implantation, while sparing Mo-MF, did not affect tumor cell seeding but significantly reduced Treg numbers, dampened the Treg regulatory program, promoted the accumulation of CD8+ T cells in tumor lesions, and reduced tumor invasiveness and growth. During tumor growth, TRMF redistributed at the periphery of the TME, which becomes dominated by Mo-MF both in mouse and human NSCLC lesions, and TRMF depletion in later stage tumors, had little effect on tumor growth. This study identifies the distinct contribution of the TRMF lineage to early lung cancer invasiveness and establish TRMF as a potential novel target to treat early lung cancer lesions.
Project description:Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer death worldwide, of which approximately 85% are non-small cell lung cancer (NSCLC). The overall survival (OS) of patients with advanced NSCLC was significantly prolonged with immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) axis. For early-stage lung cancer, the 5-year survival rate for patients ranges from 80% in stage IA to 41% in stage IIIA, and many cases relapse after surgical resection. Currently, multiple clinical trials have manifested the encouraging efficacy of neoadjuvant immunotherapy in stage I-IIIA resectable NSCLC. However, the effect of immunotherapy in ultra early-stage NSCLC patients with micro-invasive or even pre-invasive lesions remains unclear. In this study, we aimed to evaluate the activity and safety of sintilimab on high-risk ground glass opacity lesions in multiple primary lung cancer patients.