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Tumor draining lymph node immunophenotype corresponds with primary tumor characteristics in patients with non-small cell lung cancer [Meeting Abstract]

Murthy, V; Tsay, J; Minehart, J; Mangalick, K; Bessich, J; Michaud, G; Curotto, De Lafaille M; Wong, K; Goparaju, C; Pass, H; Sterman, D
Background: There is growing appreciation for the role of tumordraining lymph nodes (TDLN) in the dynamic of immuno-editing orchestrated by non-small cell lung cancers (NSCLC). By comparing Tcell subsets and gene expression in TDLN and non-draining lymph nodes (NDLN), we aim to determine whether there is tumor-regional variation in immunophenotype. Method: Patients undergoing endobronchial ultrasound-guided transbronchial needle aspiration for the diagnosis/staging of NSCLC were recruited. Aspirates were obtained from TDLN (N1/N2 nodes with increased fluorodeoxyglucose-F-18 (FDG) avidity and/or enlarged >1cm) and NDLN (non-enlarged/non- FDG-avid N2/N3 nodes) along with peripheral blood. Samples were stained with fluorophore-conjugated antibodies (CD4-FITC, CD8-V450, CD25-PECy7, CD127-APCR700, CD45RO-PECF594) and analyzed by flow cytometry. CD4+CD25- and CD8+ effector T-cells (Teff) were sorted. Gene expression profiling was performed on sorted Teff using the NanostringTM platform to measure differential expression between TDLN and NDLNs. Result: We compared T-cell subpopulations in TDLN and paired NDLN from 16 subjects. There were significantly fewer CD4+ T-cells in TDLN vs NDLN (10.1% vs 28.9%, p=0.0039), with more Tregs (12.1% vs 7.3%, p=0.1563) suggesting a pattern of tumorregional immunosuppression in the TDLN. This was more consistent when tumor histology was adenocarcinoma compared to squamous cell cancer with respect to both depletion of Teff and higher proportion of Tregs (Fig 1). A more immunosuppressive TDLN phenotype was also observed with high tumor PD-L1 expression (>50%), with 36% fewer CD4+ T-cells in TDLN relative to paired NDLN when PD-L1 expression was high relative to just 3.2% fewer CD4+ T-cells with low PD-L1 expression. Gene expression in Teff has preliminarily demonstrated upregulation of genes mediating T-cell exhaustion (CTLA-4, PD-1, TGFb) and downregulation of co-stimulatory/recruitment factors (CD28, ICOS, ICAM2) in TDLN suggesting impaired activation of tumorregional Teff. Conclusion: Our findings suggest that TDLNs in patients with NSCLC display a tolerogenic phenotype, with more marked immunosuppression in the setting of adenocarcinoma and high tumor PD-L1 expression. (Figure Presented)
EMBASE:620147988
ISSN: 1556-1380
CID: 2926612

The preclinical and clinical activity of poziotinib, a potent, selective inhibitor of EGFR Exon 20 Mutant NSCLC [Meeting Abstract]

Elamin, Y; Robichaux, J; Lam, V; Tsao, A; Lu, C; Blumenschein, G; Kurie, J; Brahmer, J; Li, S; Chen, T; Estrada-Bernal, A; Truini, A; Nilsson, M; Le, A; Tan, Z; Zhang, S; Doebele, R; Politi, K; Yang, Z; Liu, S; Wong, K; Heymach, J
Background: Approximately 10% of EGFR mutant NSCLCs have an insertion/mutation in exon 20 of EGFR resulting in primary resistance to currently available tyrosine kinase inhibitors (TKIs). We previously reported that the structural features of poziotinib could potentially enable it to circumvent the steric hindrance induced by exon 20 mutations. Here we further characterize the preclinical activity of poziotinib and report on initial clinical activity of poziotinib in patients with EGFR exon 20 mutations from an ongoing phase II study. Method: We evaluated poziotinib activity in vitro using human NSCLC cell lines and the BAF3 model as well as several patient-derived xenograft (PDX) models and genetically engineered mouse models (GEMMs) of exon 20 insertion. We launched a phase 2 investigator-initiated trial of poziotinib in patients with metastatic NSCLC with EGFR exon 20 insertions (NCT03066206). Result: In vitro poziotinib was approximately 100x more potent than osimertinib and 40x more potent than afatinib against a common panel of EGFR exon 20 insertions. Furthermore, it had w65-fold greater potency against common exon 20 insertions compared with EGFR T790M mutations; 3rd generation inhibitors osimertinib, EGF816, and rociletinib were all significantly less potent for exon 20 mutations/ insertions compared with T790M. in vivo poziotinib led to >85% reduction in tumor burden in GEM models of EGFR exon 20 insertion (D770insNPG) NSCLC and the PDX model LU0387 (H773insNPH). To date, 8 platinum-refractory patients with EGFR exon 20 insertion mutation metastatic NSCLC have been enrolled in the clinical trial and treated with poziotinib at a dose of 16 mg PO daily. Two patients have reached the first interval-imaging time point (at 8 weeks of therapy per protocol). Both patients exhibited dramatic partial response, with one patient reporting improvement in dyspnea and cough at one week of therapy. In this early stage of the study, one case of grade 3 paronchycia was observed. One additional platinum- and erlotinib-refractory patient with EGFR exon 20 insertion was treated with poziotinib on compassionate basis. The patient achieved partial response after three weeks of treatment. Conclusion: Poziotinib has selective activity against EGFR exon 20 mutations and potent activity in cell lines, PDX, and GEM models. Three platinum-refractory patients with EGFR exon 20 mutations have been treated thus far and are evaluable for response; all three had partial responses at the time of the initial scan. Updated data from the ongoing phase 2 clinical trial of poziotinib will be presented at the meeting
EMBASE:620148168
ISSN: 1556-1380
CID: 2926602

Interleukin-17a promotes lung tumor progression through neutrophil attraction to tumor sites and mediating resistance to PD-1 blockade [Meeting Abstract]

Akbay, E; Koyama, S; Dranoff, G; Wong, K
Background: Proinflammatory cytokine Interleukin (IL)-17A (IL-17A) is the prototypical member of the IL-17 family of pro-inflammatory cytokines. It is produced by Th17 cells, CD8 T cells, gdT cells, and Natural Killer (NK) cells in the tumor microenvironment. The inflammatory milieu can contribute to lung cancer growth by further production of tumor promoting cytokines, reduction in cytotoxic T cells, and development of myeloid derived suppressor cells. IL-17A and its receptors are expressed across different tumor types; however, their exact role in tumor development, progression, and response to therapeutic regimens is unclear. IL-17A is overexpressed in a subset of patients with lung cancer. We hypothesized that IL-17A promotes a protumorigenic inflammatory phenotype, and inhibits anti-tumor immune responses. Method: IL-17A is expressed at high levels in a subset of lung cancers. Interestingly, we observed that IL-17A could not be detected in Bronchoalveolar lavage fluids (BALFs) from immunocompetent mouse lung cancer models. To characterize the role of IL-17A in Kras mutant lung tumors, we developed a mouse model of chronic inflammation that more closely resembles human KRAS mutant lung cancer through expressing IL-17A constitutively in the lung epithelium and then introducing this allele into lox-stop-lox Kras G12D mutant mice. We performed immune phenotyping of mouse lungs, survival analysis, and treatment studies with antibodies either blocking PD-1 or IL6, or depleting neutrophils. To support preclinical findings, we analyzed human gene expression datasets and immune profiled patient lung tumors. Result: Tumors in IL-17:Kras G12Dmice grew more rapidly, resulting in a significantly shorter survival as compared to Kras G12D. IL-6, G-CSF, MFG-E8, and CXCL1 were increased in the lungs of IL17:Kras mice. Time course analysis revealed that tumor-associated neutrophils were significantly elevated, and lymphocyte recruitment was significantly reduced in IL17:Kras G12D mice as compared to Kras G12D. In therapeutic studies PD-1 blockade was not effective in treating IL-17:Kras G12D tumors. In contrast, blocking IL-6 or depleting neutrophils with an anti-Ly-6G antibody in the IL17:Kras G12D tumors resulted in a clinical response associated with T cell activation. In tumors from lung cancer patients with KRAS mutation we found a correlation among higher levels of IL-17A and the colony stimulating factor (CSF3), and a significant correlation among high neutrophil and lower T cell numbers. Conclusion: Here we show that an increase in a single cytokine, IL-17A, without additional mutations, can promote lung cancer growth by promoting inflammation, which contributes to resistance to PD-1 blockade and sensitizes tumors to cytokine/ neutrophil depletion
EMBASE:620146687
ISSN: 1556-1380
CID: 2926722

Workshop on challenges, insights, and future directions for mouse and humanized models in cancer immunology and immunotherapy: a report from the associated programs of the 2016 annual meeting for the Society for Immunotherapy of cancer

Zloza, Andrew; Karolina Palucka, A; Coussens, Lisa M; Gotwals, Philip J; Headley, Mark B; Jaffee, Elizabeth M; Lund, Amanda W; Sharpe, Arlene H; Sznol, Mario; Wainwright, Derek A; Wong, Kwok-Kin; Bosenberg, Marcus W
Understanding how murine models can elucidate the mechanisms underlying antitumor immune responses and advance immune-based drug development is essential to advancing the field of cancer immunotherapy. The Society for Immunotherapy of Cancer (SITC) convened a workshop titled, "Challenges, Insights, and Future Directions for Mouse and Humanized Models in Cancer Immunology and Immunotherapy" as part of the SITC 31st Annual Meeting and Associated Programs on November 10, 2016 in National Harbor, MD. The workshop focused on key issues in optimizing models for cancer immunotherapy research, with discussions on the strengths and weaknesses of current models, approaches to improve the predictive value of mouse models, and advances in cancer modeling that are anticipated in the near future. This full-day program provided an introduction to the most common immunocompetent and humanized models used in cancer immunology and immunotherapy research, and addressed the use of models to evaluate immune-targeting therapies. Here, we summarize the workshop presentations and subsequent panel discussion.
PMCID:5604351
PMID: 28923102
ISSN: 2051-1426
CID: 4192882

Gemcitabine and Chk1 Inhibitor AZD7762 Synergistically Suppress the Growth of Lkb1-Deficient Lung Adenocarcinoma

Liu, Yan; Li, Yuyang; Wang, Xiaoen; Liu, Feiyang; Gao, Peng; Quinn, Max M; Li, Fei; Merlino, Ashley A; Benes, Cyril; Liu, Qingsong; Gray, Nathanael S; Wong, Kwok-Kin
Cells lacking the tumor suppressor gene LKB1/STK11 alter their metabolism to match the demands of accelerated growth, leaving them highly vulnerable to stress. However, targeted therapy for LKB1-deficient cancers has yet to be reported. In both Kras/p53/Lkb1 cell lines and a genetically engineered mouse model of Kras/p53/Lkb1-induced lung cancer, much higher rates of DNA damage occur, resulting in increased dependence on Chk1 checkpoint function. Here we demonstrate that short-term treatment with the Chk1 inhibitor AZD7762 reduces metabolism in pembrolizumab tumors, synergizing with the DNA-damaging drug gemcitabine to reduce tumor size in these models. Our results offer preclinical proof of concept for use of a Chk1 inhibitor to safely enhance the efficacy of gemcitabine, particularly in aggressive KRAS-driven LKB1-deficient lung adenocarcinomas. Cancer Res; 77(18); 5068-76. (c)2017 AACR.
PMCID:5600859
PMID: 28754670
ISSN: 1538-7445
CID: 2708252

Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4

Dai, Xiangpeng; Gan, Wenjian; Li, Xiaoning; Wang, Shangqian; Zhang, Wei; Huang, Ling; Liu, Shengwu; Zhong, Qing; Guo, Jianping; Zhang, Jinfang; Chen, Ting; Shimizu, Kouhei; Beca, Francisco; Blattner, Mirjam; Vasudevan, Divya; Buckley, Dennis L; Qi, Jun; Buser, Lorenz; Liu, Pengda; Inuzuka, Hiroyuki; Beck, Andrew H; Wang, Liewei; Wild, Peter J; Garraway, Levi A; Rubin, Mark A; Barbieri, Christopher E; Wong, Kwok-Kin; Muthuswamy, Senthil K; Huang, Jiaoti; Chen, Yu; Bradner, James E; Wei, Wenyi
The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3SPOP earmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer-associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations.
PMID: 28805820
ISSN: 1546-170x
CID: 5381112

Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C

Zeng, Mei; Lu, Jia; Li, Lianbo; Feru, Frederic; Quan, Chunshan; Gero, Thomas W; Ficarro, Scott B; Xiong, Yuan; Ambrogio, Chiara; Paranal, Raymond M; Catalano, Marco; Shao, Jay; Wong, Kwok-Kin; Marto, Jarrod A; Fischer, Eric S; Janne, Pasi A; Scott, David A; Westover, Kenneth D; Gray, Nathanael S
Targeted covalent small molecules have shown promise for cancers driven by KRAS G12C. Allosteric compounds that access an inducible pocket formed by movement of a dynamic structural element in KRAS, switch II, have been reported, but these compounds require further optimization to enable their advancement into clinical development. We demonstrate that covalent quinazoline-based switch II pocket (SIIP) compounds effectively suppress GTP loading of KRAS G12C, MAPK phosphorylation, and the growth of cancer cells harboring G12C. Notably we find that adding an amide substituent to the quinazoline scaffold allows additional interactions with KRAS G12C, and remarkably increases the labeling efficiency, potency, and selectivity of KRAS G12C inhibitors. Structural studies using X-ray crystallography reveal a new conformation of SIIP and key interactions made by substituents located at the quinazoline 2-, 4-, and 7-positions. Optimized lead compounds in the quinazoline series selectively inhibit KRAS G12C-dependent signaling and cancer cell growth at sub-micromolar concentrations.
PMID: 28781124
ISSN: 2451-9456
CID: 2664012

Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non-small Cell Lung Cancer

Adeegbe, Dennis; Liu, Yan; Lizotte, Patrick H; Kamihara, Yusuke; Aref, Amir R; Almonte, Christina; Dries, Ruben; Li, Yuyang; Liu, Shengwu; Wang, Xiaoen; Warner-Hatten, Tiquella; Castrillon, Jessica; Yuan, Guo-Cheng; Poudel-Neupane, Neermala; Zhang, Haikuo; Guerriero, Jennifer L; Han, Shiwei; Awad, Mark M; Barbie, David A; Ritz, Jerome; Jones, Simon S; Hammerman, Peter S; Bradner, James E; Quayle, Steven N; Wong, Kwok-Kin
Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. Herein we evaluated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response. By evaluating human peripheral blood and NSCLC tumors, we show that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes that support enhanced T cell activation and improved function of antigen presenting cells. The bromodomain inhibitor JQ1 attenuated CD4+Foxp3+ T regulatory cell suppressive function and synergized with ricolinostat to facilitate immune-mediated tumor growth arrest, leading to prolonged survival of mice with lung adenocarcinomas. Collectively, our findings highlight the immunomodulatory effects of two epigenetic modifiers that, together, promote T cell-mediated anti-tumor immunity and demonstrate their therapeutic potential for treatment of NSCLC.
PMCID:5540748
PMID: 28408401
ISSN: 2159-8290
CID: 2528362

Interleukin-17A Promotes Lung Tumor Progression Through Neutrophil Attraction to Tumor Sites and Mediating Resistance to PD-1 Blockade

Akbay, Esra A; Koyama, Shohei; Liu, Yan; Dries, Ruben; Bufe, Lauren E; Silkes, Michael; Alam, Md Maksudul; Magee, Dillon M; Jones, Robert; Jinushi, Masahisa; Kulkarni, Meghana; Carretero, Julian; Wang, Xiaoen; Warner-Hatten, Tiquella; Cavanaugh, Jillian D; Osa, Akio; Kumanogoh, Atsushi; Freeman, Gordon J; Awad, Mark M; Christiani, David C; Bueno, Raphael; Hammerman, Peter S; Dranoff, Glenn; Wong, Kwok-Kin
HYPOTHESIS: Proinflammatory cytokine Interleukin (IL)-17A (IL-17A) is overexpressed in a subset of patients with lung cancer. We hypothesized that IL-17A promotes a pro-tumorigenic inflammatory phenotype, and inhibits anti-tumor immune responses. EXPERIMENTAL DESIGN: We generated bi-transgenic mice expressing a conditional IL-17A allele along with conditional KrasG12D and performed immune phenotyping of mouse lungs, survival analysis, and treatment studies with antibodies either blocking PD-1 or IL6, or depleting neutrophils. To support preclinical findings, we analyzed human gene expression datasets and immune profiled patient lung tumors. RESULTS: Tumors in IL-17:KrasG12D mice grew more rapidly, resulting in a significantly shorter survival as compared to KrasG12D. IL-6, G-CSF, MFG-E8, and CXCL1 were increased in the lungs of IL17:Kras mice. Time course analysis revealed that tumor-associated neutrophils (TANs) were significantly elevated, and lymphocyte recruitment was significantly reduced in IL17:KrasG12D mice as compared to KrasG12D. In therapeutic studies PD-1 blockade was not effective in treating IL-17:KrasG12D tumors. In contrast, blocking IL-6 or depleting neutrophils with an anti-Ly-6G antibody in the IL17:KrasG12D tumors resulted in a clinical response associated with T cell activation. In tumors from lung cancer patients with KRAS mutation we found a correlation among higher levels of IL-17A and the colony stimulating factor (CSF3), and a significant correlation among high neutrophil and lower T cell numbers. CONCLUSIONS: Here we show that an increase in a single cytokine, IL-17A, without additional mutations, can promote lung cancer growth by promoting inflammation, which contributes to resistance to PD-1 blockade and sensitizes tumors to cytokine/neutrophil depletion.
PMCID:5532066
PMID: 28483607
ISSN: 1556-1380
CID: 2548902

Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2

Zhang, Haikuo; Fillmore Brainson, Christine; Koyama, Shohei; Redig, Amanda J; Chen, Ting; Li, Shuai; Gupta, Manav; Garcia-de-Alba, Carolina; Paschini, Margherita; Herter-Sprie, Grit S; Lu, Gang; Zhang, Xin; Marsh, Bryan P; Tuminello, Stephanie J; Xu, Chunxiao; Chen, Zhao; Wang, Xiaoen; Akbay, Esra A; Zheng, Mei; Palakurthi, Sangeetha; Sholl, Lynette M; Rustgi, Anil K; Kwiatkowski, David J; Diehl, J Alan; Bass, Adam J; Sharpless, Norman E; Dranoff, Glenn; Hammerman, Peter S; Ji, Hongbin; Bardeesy, Nabeel; Saur, Dieter; Watanabe, Hideo; Kim, Carla F; Wong, Kwok-Kin
Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, DeltaNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions. The pattern of high EZH2, but low H3K27me3 mark, is also prevalent in human lung SCC and SCC regions within ADSCC tumours. Using FACS-isolated populations, we demonstrate that bronchioalveolar stem cells and club cells are the likely cells-of-origin for SCC transitioned tumours. These findings shed light on the epigenetics and cellular origins of lineage-specific lung tumours.
PMCID:5385585
PMID: 28387316
ISSN: 2041-1723
CID: 2521692