Project description:Immune checkpoint blockade (ICB) with PD1 or PDL1 antibodies has been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of the patients respond and sustained remissions are rare. Both chemotherapy and anti-angiogenic drugs may improve tumor response to ICB in mouse models and patients with cancer. Here, we used genetically engineered mouse models of KrasG12D/p53null NSCLC, including a mismatch repair-deficient variant (KrasG12D/p53null/Msh2null) with higher mutational burden, and longitudinal imaging to study tumor response and resistance to combinations of ICB, anti-angiogenic therapy, and chemotherapy. Anti-angiogenic blockade of VEGFA and angiopoietin-2 markedly slowed progression of established tumors but, contrary to findings in other mouse cancer models, addition of a PD1 or PDL1 antibody was not beneficial and even accelerated progression of some of the tumors. We found that anti-angiogenic treatment facilitated tumor infiltration by PD1+ regulatory T cells (T-regs), which were more efficiently targeted by the PD1 antibody than CD8+ T cells. Both tumor-associated macrophages (TAMs) of bone-marrow origin, which are CSF1R-dependent, and TAMs of alveolar origin, which are sensitive to cisplatin, contributed to establishing a TGFB-rich tumor microenvironment that supported PD1+ T-regs. Dual TAM targeting with a combination of cisplatin and a CSF1R inhibitor fully abated T-regs, redirected the PD1 antibody to CD8+ T cells, and improved the efficacy of anti-angiogenic immunotherapy, achieving regression of the majority of the tumors.
Project description:To investigate the chemokines expressed by the KP cancer line and to compare it to chemokines expressed in lung tissues upon inoculation of KP tumor cells
Project description:YAP depletion in the KP tumor system results in smaller tumors and delayed tumor latency. We used microarrays to investigate changes in global gene expression due to YAP1 loss in KP tumors
Project description:The study involves whole exome sequencing of 20 primary tumors obtained from lung squamous carcinoma patients of Indian origin. With this, we aim to describe the mutational profile of this specific subset of lung cancer patients. This knowledge will further allow us to gain an insight into potentially actionable genomic alterations prevalent in Indian lung squamous carcinoma.
Project description:Purpose: determine RNA expression differences in an unbiased fashion between UPS tumors derived from LSL-KrasG12D;Trp53-/- (KP) mice, and UPS tumors derived from LSL-KrasG12D;Trp53-/-;Epas1-/- (KPH2) mice. Epas1 encodes HIF-2alpha protein. RNA-seq was performed on KP (n = 4) and KPH2 (n = 4) derived UPS tumors using Illumina HiSeq 2000.
Project description:Genetically engineered mouse models (GEMM) of cancer are powerful tools to study multiple aspects of caner biology. We developed a novel GEMM for lung squamous cell carcinoma (LSCC) by genetically combining overexpression of Sox2 with loss of Lkb1: Rosa26LSL-Sox2-IRES-GFP;Lkb1fl/fl (SL). We compared gene expression profiles of SL lung tumors with normal mouse lung tissue, mouse lung adenocarcinoma (LADC) tumors from KrasLSL-G12D/+;Trp53fl/fl (KP), mouse LSCC tumors from Lkb1fl/fl;Ptenfl/fl (LP) model as well as Lenti-Sox2-Cre Lkb1fl/fl.