42 results on '"Keerthivasan S"'
Search Results
2. Immersive Virtual Reality Platform for Robot-Assisted Antenatal Ultrasound Scanning.
- Author
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Shyam A, Aparna Purayath, Keerthivasan S, Akash S. M, Aswathaman Govindaraju, Manojkumar Lakshmanan, and Mohanasankar Sivaprakasam
- Published
- 2023
- Full Text
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3. End to End Pedestrian Features Detection for Self Driving Cars
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Sri Krishna, U., Keerthivasan, S., Prudhvi, Kilari, Senthilkumar, Radha, Vijayalakshmi, U., Kacprzyk, Janusz, Series Editor, Gomide, Fernando, Advisory Editor, Kaynak, Okyay, Advisory Editor, Liu, Derong, Advisory Editor, Pedrycz, Witold, Advisory Editor, Polycarpou, Marios M., Advisory Editor, Rudas, Imre J., Advisory Editor, Wang, Jun, Advisory Editor, Senjyu, Tomonobu, editor, So–In, Chakchai, editor, and Joshi, Amit, editor
- Published
- 2023
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4. High Spectrum and Efficiency Improved Structured Compressive Sensing-Based Channel Estimation Scheme for Massive MIMO Systems
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Baranidharan, V., Raju, C., Naveen Kumar, S., Keerthivasan, S. N., Isaac Samson, S., Xhafa, Fatos, Series Editor, Hemanth, D. Jude, editor, Pelusi, Danilo, editor, and Vuppalapati, Chandrasekar, editor
- Published
- 2022
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5. India's 2021 differentiated TB care guidance: Is it feasible to implement and act upon?
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Shewade, Hemant Deepak, Frederick, Asha, Kalyanasundaram, Madhanraj, Ravichandran, Prabhadevi, Lokesh, S., Suma, K.V., Aarthi, S., Kiruthika, G., Chadwick, Joshua, Rajasekar, T. Daniel, Gayathri, K., Vijayaprabha, R., Pathinathan, Delphina Peter, Nivetha, M. Bhavani, Chidambaram, Deiveegan, Pradeep, S. Kiran, Bhatnagar, Tarun, Devika, Shanmugasundaram, Rajkumar, S., Sakthivel, M., Mathavi, T., Vellasamy, S., Rajaprakash, A.R., Ganapathy, S., Sundaralingam, K., Savithri, S., Sudha, G., Balasubramaniam, M., Megala, B., Keerthivasan, S., Arunchandar, V., Mallan, Ganga, Khaleel, A. Muhammed, Anbanantham, K., Natesh, S., Bairavi, V., Krishnamoorthy, K., Hameed, O.M. Rahman Shahul, Sathishkumar, P., Saravanan, P., Illakiyaselvan, P.T., Praveenkumar, S., Murugan, S., Ganeshkumar, K., Manoj, G., Sivaprakasam, A., Sangamithira, G., Chandrika, A., Sacred Selvin, A. Alffer, Ranjini, S.V. Asha, Babu, K. Anand, Arunshankar, V., Selvavinayagam, T.S., Ramachandran, Ranjani, and Murhekar, Manoj V.
- Published
- 2023
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6. Experimental investigation of reinforced concrete by bamboo scrimber under flexural load
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Soundharya, T., Antony, Alrin, Jayaram, AR, Keerthivasan, S., and Sanjay, S.
- Published
- 2023
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7. High Spectrum and Efficiency Improved Structured Compressive Sensing-Based Channel Estimation Scheme for Massive MIMO Systems
- Author
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Baranidharan, V., primary, Raju, C., additional, Naveen Kumar, S., additional, Keerthivasan, S. N., additional, and Isaac Samson, S., additional
- Published
- 2022
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- View/download PDF
8. Internet of Things and Blockchain Based Distributed Energy Management of Smart Micro-grids
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Raju, Leo, Balaji, V., Keerthivasan, S., Keerthivasan, C., Xhafa, Fatos, Series Editor, Pandian, A. Pasumpon, editor, Palanisamy, Ram, editor, and Ntalianis, Klimis, editor
- Published
- 2020
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9. Immersive Virtual Reality Platform for Robot-Assisted Antenatal Ultrasound Scanning
- Author
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Shyam, A, primary, Purayath, Aparna, additional, Keerthivasan, S, additional, Akash, S M, additional, Govindaraju, Aswathaman, additional, Lakshmanan, Manojkumar, additional, and Sivaprakasam, Mohanasankar, additional
- Published
- 2023
- Full Text
- View/download PDF
10. Internet of Things and Blockchain Based Distributed Energy Management of Smart Micro-grids
- Author
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Raju, Leo, primary, Balaji, V., additional, Keerthivasan, S., additional, and Keerthivasan, C., additional
- Published
- 2020
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11. Sorting of Fruits/Vegetables using Convolutional Neural Network: A Review
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Shanmugam, M, primary, Venusamy, Kanagaraj, additional, Anand, M, additional, Keerthivasan, S, additional, and Senthuran, B, additional
- Published
- 2023
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12. Assessment of Salinity Tolerance in Greengram [Vigna radiata (L.) Wilczek]
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Shanthi, P., primary, Parameshwaran, M., additional, Umadevi, M., additional, Aadhilakshmi, S., additional, and Keerthivasan, S., additional
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- 2023
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13. Implementation of Mobile App for Laundry 'Super-Dry'
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Deepthi L. R, Sundar S, Keerthivasan S, Sachin Ramsangu S, and Vikram E L
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Service (business) ,Laundry ,business.industry ,Order (business) ,Online payment ,Mobile phone ,Internet privacy ,Mobile apps ,Clothing ,business - Abstract
In this modernised world, everything is done within a tap of a mobile phone. Each service is offering online services for their customers. Actually saying we became much lazier due to these technologies that's where it comes the ‘digital-world’. Contacting a dhobi, waiting for his arrival and paying him, all these costs valuable time of a working people. And in this pandemic situation physical contact is dangerous. There are laundry services and they do not provide its service online. To avoid this problem we have created a dhobi service app called “Superdry”. One of our motive of building this Laundry Application is to provide employment to those washer-men who are unemployed. Through this app a customer can place order for various laundry services. The dhobi will collect the clothes from the customer house and after washing, will deliver it back. And the customer can make an online payment or even can pay on delivery. Here the time is saved and the contactless service is achieved. Here both the customer and the dhobi are benefited.
- Published
- 2021
14. Crime Prediction and Analysis.
- Author
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Sriraam, R. Karthik, Keerthivasan, S. M., Sukant, K., and Krishnamoorthy, A.
- Subjects
- *
CRIME analysis , *HOMICIDE rates , *SUPPORT vector machines , *CRIME statistics , *CRIME prevention , *ARTIFICIAL neural networks , *CRIMINAL methods - Abstract
The systematic technique used to detect and analyze crime patterns and trends is called crime analysis and prevention. The proposed model will be able to predict regions that have a high chance of crime occurrence. Crime data specialists can assist police officers in stopping crime more quickly. Our goal is to develop methods that can forecast homicide activities based on demographic and economic data from a specific area. In this project, we use a classification and clustering algorithm to build an effective crime prediction model. Support vector networks, multivariate time-series data, and artificial neural networks are some of the prediction approaches that can be used to test the efficiency of prediction models. We use multiple algorithms for classification and clustering and then we compare with accuracy. To measure the out-oftraining effectiveness of classifiers, we use a ten-fold cross-validation approach. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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15. Targeting molecular mediators of T cell exclusion for effective immunotherapy in ovarian cancer
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Wang, Y., primary, Desbois, M., additional, Udyavar, A., additional, Ryner, L., additional, Kozlowski, C., additional, Guan, Y., additional, Dürrbaum, M., additional, Lu, S., additional, Fortin, J.-P., additional, Koeppen, H., additional, Ziai, J., additional, Chang, C.-W., additional, Lo, A., additional, Keerthivasan, S., additional, Plante, M., additional, Bais, C., additional, Hegde, P., additional, Daemen, A., additional, and Turley, S., additional
- Published
- 2019
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16. Multi Agent Systems and Arduino based Smart Micro-grid Test bed.
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Raju, Leo, Morais, Antony Amalraj, Balaji, V., and Keerthivasan, S.
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LOAD management (Electric power) ,ENERGY consumption ,GLOBAL optimization - Abstract
The objective of this paper is implementation of smart micro-grid test bed using Multi Agent System (MAS) and Arduino micro controller and verify smart grid features. Three micro-grids are interconnected to form a virtual grid and smart grid features and flexibilities are incorporated in the network to form a smart micro-grid. A multi-agent approach is used to address the issues of complexity and flexibility in the network. Decentralized MAS provides flexibilities under turbulent environmental conditions and the flexibilities are identified and communicated to a higher level so that the control actions are decided and communicated to the appropriate level for taking actions to reduce the stress in the network. The consumer can choose the best resources available across the regions for economic and environmental optimization. Demand side management is implemented in a distributed environment for optimal use of energy. The optimization does not involve each end user only as an individual but empowers them to participate in a larger community for global optimization. The scope of the optimization is to reduce the costs associated with the energy usage of end user. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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17. India's 2021 differentiated TB care guidance: Is it feasible to implement and act upon?
- Author
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Shewade, Hemant Deepak, Frederick, Asha, Kalyanasundaram, Madhanraj, Ravichandran, Prabhadevi, Lokesh, S., Suma, K.V., Aarthi, S., Kiruthika, G., Chadwick, Joshua, Rajasekar, T. Daniel, Gayathri, K., Vijayaprabha, R., Pathinathan, Delphina Peter, Nivetha, M. Bhavani, Chidambaram, Deiveegan, Pradeep, S. Kiran, Bhatnagar, Tarun, Devika, Shanmugasundaram, Rajkumar, S., Sakthivel, M., Mathavi, T., Vellasamy, S., Rajaprakash, A.R., Ganapathy, S., Sundaralingam, K., Savithri, S., Sudha, G., Balasubramaniam, M., Megala, B., Keerthivasan, S., Arunchandar, V., Mallan, Ganga, Khaleel, A. Muhammed, Anbanantham, K., Natesh, S., Bairavi, V., Krishnamoorthy, K., Hameed, O.M. Rahman Shahul, Sathishkumar, P., Saravanan, P., Illakiyaselvan, P.T., Praveenkumar, S., Murugan, S., Ganeshkumar, K., Manoj, G., Sivaprakasam, A., Sangamithira, G., Chandrika, A., Sacred Selvin, A. Alffer, Ranjini, S.V. Asha, Babu, K. Anand, Arunshankar, V., Selvavinayagam, T.S., Ramachandran, Ranjani, and Murhekar, Manoj V.
- Abstract
In 2021, India's national tuberculosis (TB) elimination programme recommended severity assessment using 16 indicators (involving clinical, laboratory and radiological assessment) for all TB patients at diagnosis. Patients with a total score more than one or emergency criteria were eligible for referral and inpatient care (called as severely ill). This guidance is yet to be implemented statewide in India. Even in ideal settings, we wanted to understand the feasibility of implementing and acting upon the findings of severity assessment using 16 indicators. Specifically, how many would be assessed and eligible for inpatient care, followed by early deaths (within two months) among those with and without severe illness.
- Published
- 2024
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18. Prospective study of timing and pattern of bacteria and viruses in the nasopharyngeal microbiome in a birth cohort
- Author
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Mathew, J.L., primary, Keerthivasan, S., additional, Agarwal, A., additional, Sarkar, S., additional, Ratho, R., additional, Gautam, V., additional, Singhi, S., additional, Dutta, S., additional, and Nilsson, A., additional
- Published
- 2018
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19. 1875PD - Targeting molecular mediators of T cell exclusion for effective immunotherapy in ovarian cancer
- Author
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Wang, Y., Desbois, M., Udyavar, A., Ryner, L., Kozlowski, C., Guan, Y., Dürrbaum, M., Lu, S., Fortin, J.-P., Koeppen, H., Ziai, J., Chang, C.-W., Lo, A., Keerthivasan, S., Plante, M., Bais, C., Hegde, P., Daemen, A., and Turley, S.
- Published
- 2019
- Full Text
- View/download PDF
20. Transcriptional upregulation of human cathepsin L by VEGF in glioblastoma cells
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Keerthivasan, S., primary, Keerthivasan, G., additional, Mittal, S., additional, and Chauhan, S.S., additional
- Published
- 2007
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21. A case report of Mounier-Kuhn syndrome
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Keerthivasan Sivanmani
- Subjects
Bronchiectasis ,diverticulosis ,tracheobronchomegaly ,Diseases of the respiratory system ,RC705-779 - Abstract
Mounier-Kuhn syndrome is a congenital abnormality characterized by tracheobronchomegaly as a result of atrophy or absence of elastic fibers and thinning of smooth muscle layer in trachea and main bronchi. The usual presentation is one of recurrent respiratory tract infections with a broad spectrum of functional impairment ranging from minimal disease with preservation of lung function to severe disease in the form of bronchiectasis. We describe a case of an elderly man who presented with a recurrent respiratory infection who was subsequently diagnosed as Mounier-Kuhn syndrome.
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- 2017
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22. Pulmonary Alveolar Microlithiasis.
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Gayathri, B. and Keerthivasan, S.
- Subjects
- *
PULMONARY alveoli , *TOMOGRAPHY , *X-rays , *LUNG diseases , *CHEST X rays , *PLEURA , *DISEASES - Abstract
Pulmonary alveolar microlithiasis (PAM) is a rare idiopathic disease characterized by microliths in the lungs which is usually asymptomatic and often diagnosed incidentally. Here we discuss a case of a young woman while evaluating for surgery presented with an abnormal chest X ray of bilateral diffuse nodular opacities. Patient was completely asymptomatic. High resolution CT scan revealed crazy paving pattern, black pleura sign, and pleural calcification typical findings of pulmonary alveolar microlithiasis. CT guided lung biopsy confirmed the diagnosis. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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23. Central precocious puberty complicating congenital adrenal hyperplasia: North Indian experience
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Devi Dayal, Anshita Aggarwal, Keerthivasan Seetharaman, and Balasubramaniyan Muthuvel
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Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Published
- 2018
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24. Design of low intricate 10-bit current steering digital to analog converter circuitry using full swing GDI
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Keerthivasan, S., Mahendra Babu, and Rajendran, T.
25. Transfer learning in a biomaterial fibrosis model identifies in vivo senescence heterogeneity and contributions to vascularization and matrix production across species and diverse pathologies.
- Author
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Cherry C, Andorko JI, Krishnan K, Mejías JC, Nguyen HH, Stivers KB, Gray-Gaillard EF, Ruta A, Han J, Hamada N, Hamada M, Sturmlechner I, Trewartha S, Michel JH, Davenport Huyer L, Wolf MT, Tam AJ, Peña AN, Keerthivasan S, Le Saux CJ, Fertig EJ, Baker DJ, Housseau F, van Deursen JM, Pardoll DM, and Elisseeff JH
- Subjects
- Humans, Mice, Animals, Phenotype, Fibroblasts, Machine Learning, Cellular Senescence genetics, Aging genetics
- Abstract
Cellular senescence is a state of permanent growth arrest that plays an important role in wound healing, tissue fibrosis, and tumor suppression. Despite senescent cells' (SnCs) pathological role and therapeutic interest, their phenotype in vivo remains poorly defined. Here, we developed an in vivo-derived senescence signature (SenSig) using a foreign body response-driven fibrosis model in a p16-CreER
T2 ;Ai14 reporter mouse. We identified pericytes and "cartilage-like" fibroblasts as senescent and defined cell type-specific senescence-associated secretory phenotypes (SASPs). Transfer learning and senescence scoring identified these two SnC populations along with endothelial and epithelial SnCs in new and publicly available murine and human data single-cell RNA sequencing (scRNAseq) datasets from diverse pathologies. Signaling analysis uncovered crosstalk between SnCs and myeloid cells via an IL34-CSF1R-TGFβR signaling axis, contributing to tissue balance of vascularization and matrix production. Overall, our study provides a senescence signature and a computational approach that may be broadly applied to identify SnC transcriptional profiles and SASP factors in wound healing, aging, and other pathologies., (© 2023. The Author(s), under exclusive licence to American Aging Association.)- Published
- 2023
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26. CD8 + T cell-intrinsic IL-6 signaling promotes resistance to anti-PD-L1 immunotherapy.
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Huseni MA, Wang L, Klementowicz JE, Yuen K, Breart B, Orr C, Liu LF, Li Y, Gupta V, Li C, Rishipathak D, Peng J, Şenbabaoǧlu Y, Modrusan Z, Keerthivasan S, Madireddi S, Chen YJ, Fraser EJ, Leng N, Hamidi H, Koeppen H, Ziai J, Hashimoto K, Fassò M, Williams P, McDermott DF, Rosenberg JE, Powles T, Emens LA, Hegde PS, Mellman I, Turley SJ, Wilson MS, Mariathasan S, Molinero L, Merchant M, and West NR
- Subjects
- Animals, Mice, B7-H1 Antigen immunology, B7-H1 Antigen therapeutic use, CD8-Positive T-Lymphocytes metabolism, Immunotherapy, Antineoplastic Agents therapeutic use, Interleukin-6 metabolism, Neoplasms immunology, Neoplasms therapy
- Abstract
Although immune checkpoint inhibitors (ICIs) are established as effective cancer therapies, overcoming therapeutic resistance remains a critical challenge. Here we identify interleukin 6 (IL-6) as a correlate of poor response to atezolizumab (anti-PD-L1) in large clinical trials of advanced kidney, breast, and bladder cancers. In pre-clinical models, combined blockade of PD-L1 and the IL-6 receptor (IL6R) causes synergistic regression of large established tumors and substantially improves anti-tumor CD8
+ cytotoxic T lymphocyte (CTL) responses compared with anti-PD-L1 alone. Circulating CTLs from cancer patients with high plasma IL-6 display a repressed functional profile based on single-cell RNA sequencing, and IL-6-STAT3 signaling inhibits classical cytotoxic differentiation of CTLs in vitro. In tumor-bearing mice, CTL-specific IL6R deficiency is sufficient to improve anti-PD-L1 activity. Thus, based on both clinical and experimental evidence, agents targeting IL-6 signaling are plausible partners for combination with ICIs in cancer patients., Competing Interests: Declaration of interests M.A.H., K.Y., L.W., J.E.K., L.L., Y.L., V.G., C.L., D.R., C.O., S.M., S.K., Y.J.C., J.P., Y.S., Z.M., B.B., E.J.F., N.L., H.K., J.Z., M.F., P.W., M.W., I.M., S.J.T., M.M., S.M., L.M., and N.R.W. are employees of Genentech, Inc. M.A.H., K.Y., L.W., J.E.K., L.L., Y.L., P.W., M.M., S.M., L.M., and N.R.W. are inventors on patents related to IL-6. P.S.H. is an employee of Foundation Medicine Inc. K.H. is an employee of Roche Products Ltd. D.F.M. reports a consulting/advisory role for Bristol-Myers Squibb, Merck, Roche/Genentech, Pfizer, Exelixis, Novartis, Eisai, X4 Pharmaceuticals, and Array BioPharma; he also reports that his home institution receives research funding from Prometheus Laboratories. T.P. reports honoraria and consulting/advisory roles with Roche/Genentech, Bristol-Myers Squibb, and Merck; consulting/advisory role with AstraZeneca and Novartis; research funding from AstraZeneca/MedImmune and Roche/Genentech; and other relationships with Ipsen and Bristol-Myers Squibb. L.E. reports honoraria from or consulting/advisory roles with AbbVie, Amgen, AstraZeneca, Bayer, Bristol Meyers Squibb, Celgene, Chugai, eTHeRNA, Genentech, Gritstone, Medimmune, Molecuvax, Macrogenics, Novartis, Peregrine, Replimune, Roche, Silverback, Syndax, and Vaccinex; she reports that her home institution receives funding from Aduro Biotech, AstraZeneca, Breast Cancer Research Foundation, Bristol Meyers Squibb, Corvus, Department of Defense, EMD Serono, Genentech, HeritX, Inc., Maxcyte, Merck, National Cancer Institute, NSABP Foundation, Roche, Tempest, Translational Breast Cancer Research Consortium. J.E.R. has received non-financial support from Roche Genentech and consulting fees from Agensys, Eli Lilly, Sanofi, and Oncogene., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2023
- Full Text
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27. Spatial Positioning and Matrix Programs of Cancer-Associated Fibroblasts Promote T-cell Exclusion in Human Lung Tumors.
- Author
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Grout JA, Sirven P, Leader AM, Maskey S, Hector E, Puisieux I, Steffan F, Cheng E, Tung N, Maurin M, Vaineau R, Karpf L, Plaud M, Begue AL, Ganesh K, Mesple J, Casanova-Acebes M, Tabachnikova A, Keerthivasan S, Lansky A, Berichel JL, Walker L, Rahman AH, Gnjatic S, Girard N, Lefevre M, Damotte D, Adam J, Martin JC, Wolf A, Flores RM, Beasley MB, Pradhan R, Muller S, Marron TU, Turley SJ, Merad M, Kenigsberg E, and Salmon H
- Subjects
- Humans, T-Lymphocytes, Tumor Microenvironment, Immunotherapy methods, Fibroblasts, Cancer-Associated Fibroblasts pathology, Lung Neoplasms pathology
- Abstract
It is currently accepted that cancer-associated fibroblasts (CAF) participate in T-cell exclusion from tumor nests. To unbiasedly test this, we used single-cell RNA sequencing coupled with multiplex imaging on a large cohort of lung tumors. We identified four main CAF populations, two of which are associated with T-cell exclusion: (i) MYH11+αSMA+ CAF, which are present in early-stage tumors and form a single cell layer lining cancer aggregates, and (ii) FAP+αSMA+ CAF, which appear in more advanced tumors and organize in patches within the stroma or in multiple layers around tumor nests. Both populations orchestrate a particular structural tissue organization through dense and aligned fiber deposition compared with T cell-permissive CAF. Yet they produce distinct matrix molecules, including collagen IV (MYH11+αSMA+ CAF) and collagen XI/XII (FAP+αSMA+ CAF). Hereby, we uncovered unique molecular programs of CAF driving T-cell marginalization, whose targeting should increase immunotherapy efficacy in patients bearing T cell-excluded tumors., Significance: The cellular and molecular programs driving T-cell marginalization in solid tumors remain unclear. Here, we describe two CAF populations associated with T-cell exclusion in human lung tumors. We demonstrate the importance of pairing molecular and spatial analysis of the tumor microenvironment, a prerequisite to developing new strategies targeting T cell-excluding CAF. See related commentary by Sherman, p. 2501. This article is highlighted in the In This Issue feature, p. 2483., (©2022 American Association for Cancer Research.)
- Published
- 2022
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28. The neutrophil protein CD177 is a novel PDPN receptor that regulates human cancer-associated fibroblast physiology.
- Author
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Astarita JL, Keerthivasan S, Husain B, Şenbabaoğlu Y, Verschueren E, Gierke S, Pham VC, Peterson SM, Chalouni C, Pierce AA, Lill JR, Gonzalez LC, Martinez-Martin N, and Turley SJ
- Subjects
- Apoptosis, Biomarkers, Tumor genetics, Cancer-Associated Fibroblasts immunology, Cancer-Associated Fibroblasts metabolism, Cell Proliferation, Colorectal Neoplasms genetics, Colorectal Neoplasms immunology, Colorectal Neoplasms metabolism, GPI-Linked Proteins genetics, GPI-Linked Proteins metabolism, Humans, Isoantigens genetics, Membrane Glycoproteins genetics, Neutrophils immunology, Neutrophils metabolism, Prognosis, Receptors, Cell Surface genetics, Survival Rate, Tumor Cells, Cultured, Biomarkers, Tumor metabolism, Cancer-Associated Fibroblasts pathology, Colorectal Neoplasms pathology, Gene Expression Regulation, Neoplastic, Isoantigens metabolism, Membrane Glycoproteins metabolism, Receptors, Cell Surface metabolism, Tumor Microenvironment
- Abstract
The cancer-associated fibroblast (CAF) marker podoplanin (PDPN) is generally correlated with poor clinical outcomes in cancer patients and thus represents a promising therapeutic target. Despite its biomedical relevance, basic aspects of PDPN biology such as its cellular functions and cell surface ligands remain poorly uncharacterized, thus challenging drug development. Here, we utilize a high throughput platform to elucidate the PDPN cell surface interactome, and uncover the neutrophil protein CD177 as a new binding partner. Quantitative proteomics analysis of the CAF phosphoproteome reveals a role for PDPN in cell signaling, growth and actomyosin contractility, among other processes. Moreover, cellular assays demonstrate that CD177 is a functional antagonist, recapitulating the phenotype observed in PDPN-deficient CAFs. In sum, starting from the unbiased elucidation of the PDPN co-receptome, our work provides insights into PDPN functions and reveals the PDPN/CD177 axis as a possible modulator of fibroblast physiology in the tumor microenvironment., Competing Interests: Y.S., S.G., V.C.P., C.C., J.R.L., and S.J.T. are Genentech employees and own shares in the Genentech/Roche group. J.L.A, S.K., B.H., E.V., S.M.P., A.A.P., L.G. and N.M.M. were employees of Roche when the data in this paper was generated.
- Published
- 2021
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29. Homeostatic functions of monocytes and interstitial lung macrophages are regulated via collagen domain-binding receptor LAIR1.
- Author
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Keerthivasan S, Şenbabaoğlu Y, Martinez-Martin N, Husain B, Verschueren E, Wong A, Yang YA, Sun Y, Pham V, Hinkle T, Oei Y, Madireddi S, Corpuz R, Tam L, Carlisle S, Roose-Girma M, Modrusan Z, Ye Z, Koerber JT, and Turley SJ
- Subjects
- Animals, Apoptosis physiology, Bone Marrow metabolism, Bone Marrow pathology, COS Cells, Cell Differentiation physiology, Cell Line, Cell Line, Tumor, Cell Lineage physiology, Cell Proliferation physiology, Chlorocebus aethiops, Female, Humans, Lung pathology, Macrophages, Alveolar pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Monocytes pathology, Myeloid Cells metabolism, Myeloid Cells pathology, Neoplasm Metastasis pathology, Proteomics methods, Signal Transduction physiology, Homeostasis physiology, Lung metabolism, Macrophages, Alveolar metabolism, Monocytes metabolism, Receptors, Immunologic metabolism
- Abstract
Myeloid cells encounter stromal cells and their matrix determinants on a continual basis during their residence in any given organ. Here, we examined the impact of the collagen receptor LAIR1 on myeloid cell homeostasis and function. LAIR1 was highly expressed in the myeloid lineage and enriched in non-classical monocytes. Proteomic definition of the LAIR1 interactome identified stromal factor Colec12 as a high-affinity LAIR1 ligand. Proteomic profiling of LAIR1 signaling triggered by Collagen1 and Colec12 highlighted pathways associated with survival, proliferation, and differentiation. Lair1
-/- mice had reduced frequencies of Ly6C- monocytes, which were associated with altered proliferation and apoptosis of non-classical monocytes from bone marrow and altered heterogeneity of interstitial macrophages in lung. Myeloid-specific LAIR1 deficiency promoted metastatic growth in a melanoma model and LAIR1 expression associated with improved clinical outcomes in human metastatic melanoma. Thus, monocytes and macrophages rely on LAIR1 sensing of stromal determinants for fitness and function, with relevance in homeostasis and disease., Competing Interests: Declarations of interests All authors are stockholders of Genentech/Roche except B.H., A.W., E.V., and S.C., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
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30. Gremlin 1 + fibroblastic niche maintains dendritic cell homeostasis in lymphoid tissues.
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Kapoor VN, Müller S, Keerthivasan S, Brown M, Chalouni C, Storm EE, Castiglioni A, Lane R, Nitschke M, Dominguez CX, Astarita JL, Krishnamurty AT, Carbone CB, Senbabaoglu Y, Wang AW, Wu X, Cremasco V, Roose-Girma M, Tam L, Doerr J, Chen MZ, Lee WP, Modrusan Z, Yang YA, Bourgon R, Sandoval W, Shaw AS, de Sauvage FJ, Mellman I, Moussion C, and Turley SJ
- Subjects
- Aged, Animals, Apoptosis genetics, Apoptosis immunology, Cell Proliferation genetics, Cell Survival genetics, Cell Survival immunology, Dendritic Cells, Follicular metabolism, Female, Fibroblasts metabolism, Gene Expression Regulation immunology, Gene Knock-In Techniques, Humans, Immunity, Cellular genetics, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins metabolism, Lymph Nodes cytology, Male, Mice, Mice, Transgenic, RNA-Seq, Single-Cell Analysis, Stromal Cells metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, Dendritic Cells, Follicular immunology, Fibroblasts immunology, Lymph Nodes immunology, Stromal Cells immunology
- Abstract
Fibroblastic reticular cells (FRCs) are specialized stromal cells that define tissue architecture and regulate lymphocyte compartmentalization, homeostasis, and innate and adaptive immunity in secondary lymphoid organs (SLOs). In the present study, we used single-cell RNA sequencing (scRNA-seq) of human and mouse lymph nodes (LNs) to identify a subset of T cell-zone FRCs defined by the expression of Gremlin1 (Grem1) in both species. Grem1-CreER
T2 knock-in mice enabled localization, multi-omics characterization and genetic depletion of Grem1+ FRCs. Grem1+ FRCs primarily localize at T-B cell junctions of SLOs, neighboring pre-dendritic cells and conventional dendritic cells (cDCs). As such, their depletion resulted in preferential loss and decreased homeostatic proliferation and survival of resident cDCs and compromised T cell immunity. Trajectory analysis of human LN scRNA-seq data revealed expression similarities to murine FRCs, with GREM1+ cells marking the endpoint of both trajectories. These findings illuminate a new Grem1+ fibroblastic niche in LNs that functions to maintain the homeostasis of lymphoid tissue-resident cDCs.- Published
- 2021
- Full Text
- View/download PDF
31. Author Correction: High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade.
- Author
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Yuen KC, Liu LF, Gupta V, Madireddi S, Keerthivasan S, Li C, Rishipathak D, Williams P, Kadel EE 3rd, Koeppen H, Chen YJ, Modrusan Z, Grogan JL, Banchereau R, Leng N, Thastrom A, Shen X, Hashimoto K, Tayama D, van der Heijden MS, Rosenberg JE, McDermott DF, Powles T, Hegde PS, Huseni MA, and Mariathasan S
- Published
- 2021
- Full Text
- View/download PDF
32. Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer.
- Author
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Desbois M, Udyavar AR, Ryner L, Kozlowski C, Guan Y, Dürrbaum M, Lu S, Fortin JP, Koeppen H, Ziai J, Chang CW, Keerthivasan S, Plante M, Bourgon R, Bais C, Hegde P, Daemen A, Turley S, and Wang Y
- Subjects
- Antigen Presentation immunology, Carcinoma, Ovarian Epithelial genetics, Carcinoma, Ovarian Epithelial metabolism, Carcinoma, Ovarian Epithelial pathology, Cell Line, Tumor, Cohort Studies, DNA Methylation, Endopeptidases, Female, Gelatinases metabolism, Gene Expression Profiling, Histocompatibility Antigens Class I metabolism, Humans, Machine Learning, Membrane Proteins metabolism, Multigene Family, Ovarian Neoplasms genetics, Ovarian Neoplasms metabolism, Ovarian Neoplasms pathology, Prognosis, RNA-Seq, Serine Endopeptidases metabolism, Stromal Cells metabolism, CD8-Positive T-Lymphocytes immunology, Carcinoma, Ovarian Epithelial immunology, Gene Expression Regulation, Neoplastic immunology, Ovarian Neoplasms immunology, Transforming Growth Factor beta metabolism, Tumor Microenvironment immunology
- Abstract
Close proximity between cytotoxic T lymphocytes and tumour cells is required for effective immunotherapy. However, what controls the spatial distribution of T cells in the tumour microenvironment is not well understood. Here we couple digital pathology and transcriptome analysis on a large ovarian tumour cohort and develop a machine learning approach to molecularly classify and characterize tumour-immune phenotypes. Our study identifies two important hallmarks characterizing T cell excluded tumours: 1) loss of antigen presentation on tumour cells and 2) upregulation of TGFβ and activated stroma. Furthermore, we identify TGFβ as an important mediator of T cell exclusion. TGFβ reduces MHC-I expression in ovarian cancer cells in vitro. TGFβ also activates fibroblasts and induces extracellular matrix production as a potential physical barrier to hinder T cell infiltration. Our findings indicate that targeting TGFβ might be a promising strategy to overcome T cell exclusion and improve clinical benefits of cancer immunotherapy.
- Published
- 2020
- Full Text
- View/download PDF
33. High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade.
- Author
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Yuen KC, Liu LF, Gupta V, Madireddi S, Keerthivasan S, Li C, Rishipathak D, Williams P, Kadel EE 3rd, Koeppen H, Chen YJ, Modrusan Z, Grogan JL, Banchereau R, Leng N, Thastrom A, Shen X, Hashimoto K, Tayama D, van der Heijden MS, Rosenberg JE, McDermott DF, Powles T, Hegde PS, Huseni MA, and Mariathasan S
- Subjects
- Adult, Antibodies, Monoclonal, Humanized therapeutic use, B7-H1 Antigen immunology, Biomarkers, Pharmacological blood, Biomarkers, Pharmacological metabolism, Biomarkers, Tumor blood, Biomarkers, Tumor metabolism, Carcinoma, Renal Cell diagnosis, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell metabolism, Carcinoma, Renal Cell mortality, Carcinoma, Transitional Cell diagnosis, Carcinoma, Transitional Cell drug therapy, Carcinoma, Transitional Cell metabolism, Carcinoma, Transitional Cell mortality, Drug Resistance, Neoplasm, Female, Humans, Interleukin-8 blood, Kidney Neoplasms diagnosis, Kidney Neoplasms drug therapy, Kidney Neoplasms metabolism, Kidney Neoplasms mortality, Male, Neoplasms metabolism, Neoplasms mortality, Prognosis, Survival Analysis, Treatment Failure, Urologic Neoplasms diagnosis, Urologic Neoplasms drug therapy, Urologic Neoplasms metabolism, Urologic Neoplasms mortality, Antineoplastic Agents, Immunological therapeutic use, B7-H1 Antigen antagonists & inhibitors, Interleukin-8 metabolism, Neoplasms diagnosis, Neoplasms drug therapy
- Abstract
Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade
1 , this has not been comprehensively evaluated in large randomized studies. Here we analyzed circulating pIL-8 and IL8 gene expression in peripheral blood mononuclear cells and tumors of patients treated with atezolizumab (anti-PD-L1 monoclonal antibody) from multiple randomized trials representing 1,445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma. High levels of IL-8 in plasma, peripheral blood mononuclear cells and tumors were associated with decreased efficacy of atezolizumab in patients with mUC and metastatic renal cell carcinoma, even in tumors that were classically CD8+ T cell inflamed. Low baseline pIL-8 in patients with mUC was associated with increased response to atezolizumab and chemotherapy. Patients with mUC who experienced on-treatment decreases in pIL-8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNA sequencing of the immune compartment showed that IL8 is primarily expressed in circulating and intratumoral myeloid cells and that high IL8 expression is associated with downregulation of the antigen-presentation machinery. Therapies that can reverse the impacts of IL-8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors.- Published
- 2020
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- View/download PDF
34. Distinct Mesenchymal Cell Populations Generate the Essential Intestinal BMP Signaling Gradient.
- Author
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McCarthy N, Manieri E, Storm EE, Saadatpour A, Luoma AM, Kapoor VN, Madha S, Gaynor LT, Cox C, Keerthivasan S, Wucherpfennig K, Yuan GC, de Sauvage FJ, Turley SJ, and Shivdasani RA
- Subjects
- Cell Proliferation, Intestinal Mucosa, Stem Cells, Intestines, Signal Transduction
- Abstract
Intestinal stem cells (ISCs) are confined to crypt bottoms and their progeny differentiate near crypt-villus junctions. Wnt and bone morphogenic protein (BMP) gradients drive this polarity, and colorectal cancer fundamentally reflects disruption of this homeostatic signaling. However, sub-epithelial sources of crucial agonists and antagonists that organize this BMP gradient remain obscure. Here, we couple whole-mount high-resolution microscopy with ensemble and single-cell RNA sequencing (RNA-seq) to identify three distinct PDGFRA
+ mesenchymal cell types. PDGFRA(hi) telocytes are especially abundant at the villus base and provide a BMP reservoir, and we identified a CD81+ PDGFRA(lo) population present just below crypts that secretes the BMP antagonist Gremlin1. These cells, referred to as trophocytes, are sufficient to expand ISCs in vitro without additional trophic support and contribute to ISC maintenance in vivo. This study reveals intestinal mesenchymal structure at fine anatomic, molecular, and functional detail and the cellular basis for a signaling gradient necessary for tissue self-renewal., Competing Interests: Declaration of Interests E.E.S., V.N.K., C.C., S.K., F.J.d.S., and S.J.T. are employees of Genentech and own shares in Roche. The other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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35. Peripheral T cell expansion predicts tumour infiltration and clinical response.
- Author
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Wu TD, Madireddi S, de Almeida PE, Banchereau R, Chen YJ, Chitre AS, Chiang EY, Iftikhar H, O'Gorman WE, Au-Yeung A, Takahashi C, Goldstein LD, Poon C, Keerthivasan S, de Almeida Nagata DE, Du X, Lee HM, Banta KL, Mariathasan S, Das Thakur M, Huseni MA, Ballinger M, Estay I, Caplazi P, Modrusan Z, Delamarre L, Mellman I, Bourgon R, and Grogan JL
- Subjects
- Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents therapeutic use, Clone Cells, Humans, Neoplasms drug therapy, Neoplasms immunology, T-Lymphocytes metabolism, Transcriptome, Lymphocytes, Tumor-Infiltrating cytology, Lymphocytes, Tumor-Infiltrating metabolism, Neoplasms pathology, Pharmacogenomic Variants, Receptors, Antigen, T-Cell genetics, T-Lymphocytes cytology
- Abstract
Despite the resounding clinical success in cancer treatment of antibodies that block the interaction of PD1 with its ligand PDL1
1 , the mechanisms involved remain unknown. A major limitation to understanding the origin and fate of T cells in tumour immunity is the lack of quantitative information on the distribution of individual clonotypes of T cells in patients with cancer. Here, by performing deep single-cell sequencing of RNA and T cell receptors in patients with different types of cancer, we survey the profiles of various populations of T cells and T cell receptors in tumours, normal adjacent tissue, and peripheral blood. We find clear evidence of clonotypic expansion of effector-like T cells not only within the tumour but also in normal adjacent tissue. Patients with gene signatures of such clonotypic expansion respond best to anti-PDL1 therapy. Notably, expanded clonotypes found in the tumour and normal adjacent tissue can also typically be detected in peripheral blood, which suggests a convenient approach to patient identification. Analyses of our data together with several external datasets suggest that intratumoural T cells, especially in responsive patients, are replenished with fresh, non-exhausted replacement cells from sites outside the tumour, suggesting continued activity of the cancer immunity cycle in these patients, the acceleration of which may be associated with clinical response.- Published
- 2020
- Full Text
- View/download PDF
36. Single-Cell RNA Sequencing Reveals Stromal Evolution into LRRC15 + Myofibroblasts as a Determinant of Patient Response to Cancer Immunotherapy.
- Author
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Dominguez CX, Müller S, Keerthivasan S, Koeppen H, Hung J, Gierke S, Breart B, Foreman O, Bainbridge TW, Castiglioni A, Senbabaoglu Y, Modrusan Z, Liang Y, Junttila MR, Klijn C, Bourgon R, and Turley SJ
- Subjects
- Animals, B7-H1 Antigen antagonists & inhibitors, B7-H1 Antigen immunology, Cancer-Associated Fibroblasts drug effects, Cancer-Associated Fibroblasts metabolism, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal immunology, Cell Line, Tumor, Cell Lineage genetics, Cell Lineage immunology, Clinical Trials as Topic, Computational Biology, Disease Models, Animal, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm immunology, Gene Expression Regulation, Neoplastic drug effects, Gene Expression Regulation, Neoplastic immunology, Humans, Immune Checkpoint Inhibitors therapeutic use, Mice, Myofibroblasts drug effects, Myofibroblasts metabolism, Pancreatic Neoplasms genetics, Pancreatic Neoplasms immunology, RNA-Seq, Single-Cell Analysis, Transforming Growth Factor beta metabolism, Treatment Outcome, Tumor Microenvironment drug effects, Tumor Microenvironment genetics, Tumor Microenvironment immunology, Cancer-Associated Fibroblasts immunology, Carcinoma, Pancreatic Ductal drug therapy, Drug Resistance, Neoplasm genetics, Immune Checkpoint Inhibitors pharmacology, Membrane Proteins metabolism, Myofibroblasts immunology, Pancreatic Neoplasms drug therapy
- Abstract
With only a fraction of patients responding to cancer immunotherapy, a better understanding of the entire tumor microenvironment is needed. Using single-cell transcriptomics, we chart the fibroblastic landscape during pancreatic ductal adenocarcinoma (PDAC) progression in animal models. We identify a population of carcinoma-associated fibroblasts (CAF) that are programmed by TGFβ and express the leucine-rich repeat containing 15 (LRRC15) protein. These LRRC15
+ CAFs surround tumor islets and are absent from normal pancreatic tissue. The presence of LRRC15+ CAFs in human patients was confirmed in >80,000 single cells from 22 patients with PDAC as well as by using IHC on samples from 70 patients. Furthermore, immunotherapy clinical trials comprising more than 600 patients across six cancer types revealed elevated levels of the LRRC15+ CAF signature correlated with poor response to anti-PD-L1 therapy. This work has important implications for targeting nonimmune elements of the tumor microenvironment to boost responses of patients with cancer to immune checkpoint blockade therapy. SIGNIFICANCE: This study describes the single-cell landscape of CAFs in pancreatic cancer during in vivo tumor evolution. A TGFβ-driven, LRRC15+ CAF lineage is associated with poor outcome in immunotherapy trial data comprising multiple solid-tumor entities and represents a target for combinatorial therapy. This article is highlighted in the In This Issue feature, p. 161 ., (©2019 American Association for Cancer Research.)- Published
- 2020
- Full Text
- View/download PDF
37. FAP Delineates Heterogeneous and Functionally Divergent Stromal Cells in Immune-Excluded Breast Tumors.
- Author
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Cremasco V, Astarita JL, Grauel AL, Keerthivasan S, MacIsaac K, Woodruff MC, Wu M, Spel L, Santoro S, Amoozgar Z, Laszewski T, Migoni SC, Knoblich K, Fletcher AL, LaFleur M, Wucherpfennig KW, Pure E, Dranoff G, Carroll MC, and Turley SJ
- Subjects
- Animals, Breast Neoplasms immunology, Cancer-Associated Fibroblasts metabolism, Cancer-Associated Fibroblasts pathology, Cell Proliferation, Endopeptidases, Female, Gene Expression Regulation, Humans, Membrane Glycoproteins metabolism, Mice, Inbred BALB C, Mice, Inbred C57BL, Nitric Oxide metabolism, Pericytes metabolism, Pericytes pathology, Stromal Cells pathology, T-Lymphocytes pathology, Breast Neoplasms pathology, Gelatinases metabolism, Membrane Proteins metabolism, Serine Endopeptidases metabolism, Stromal Cells metabolism, Tumor Microenvironment immunology
- Abstract
Cancer-associated fibroblasts (CAFs) are generally associated with poor clinical outcome. CAFs support tumor growth in a variety of ways and can suppress antitumor immunity and response to immunotherapy. However, a precise understanding of CAF contributions to tumor growth and therapeutic response is lacking. Discrepancies in this field of study may stem from heterogeneity in the composition and function of fibroblasts in the tumor microenvironment. Furthermore, it remains unclear whether CAFs directly interact with and suppress T cells. Here, mouse and human breast tumors were used to examine stromal cells expressing fibroblast activation protein (FAP), a surface marker for CAFs. Two discrete populations of FAP
+ mesenchymal cells were identified on the basis of podoplanin (PDPN) expression: a FAP+ PDPN+ population of CAFs and a FAP+ PDPN- population of cancer-associated pericytes (CAPs). Although both subsets expressed extracellular matrix molecules, the CAF transcriptome was enriched in genes associated with TGFβ signaling and fibrosis compared with CAPs. In addition, CAFs were enriched at the outer edge of the tumor, in close contact with T cells, whereas CAPs were localized around vessels. Finally, FAP+ PDPN+ CAFs suppressed the proliferation of T cells in a nitric oxide-dependent manner, whereas FAP+ PDPN- pericytes were not immunosuppressive. Collectively, these findings demonstrate that breast tumors contain multiple populations of FAP-expressing stromal cells of dichotomous function, phenotype, and location., (©2018 American Association for Cancer Research.)- Published
- 2018
- Full Text
- View/download PDF
38. NOTCH1 Can Initiate NF-κB Activation via Cytosolic Interactions with Components of the T Cell Signalosome.
- Author
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Shin HM, Tilahun ME, Cho OH, Chandiran K, Kuksin CA, Keerthivasan S, Fauq AH, Golde TE, Miele L, Thome M, Osborne BA, and Minter LM
- Abstract
T cell stimulation requires the input and integration of external signals. Signaling through the T cell receptor (TCR) is known to induce formation of the membrane-tethered CBM complex, comprising CARMA1, BCL10, and MALT1, which is required for TCR-mediated NF-κB activation. TCR signaling has been shown to activate NOTCH proteins, transmembrane receptors also implicated in NF-κB activation. However, the link between TCR-mediated NOTCH signaling and early events leading to induction of NF-κB activity remains unclear. In this report, we demonstrate a novel cytosolic function for NOTCH1 and show that it is essential to CBM complex formation. Using a model of skin allograft rejection, we show in vivo that NOTCH1 acts in the same functional pathway as PKCθ, a T cell-specific kinase important for CBM assembly and classical NF-κB activation. We further demonstrate in vitro NOTCH1 associates physically with PKCθ and CARMA1 in the cytosol. Unexpectedly, when NOTCH1 expression was abrogated using RNAi approaches, interactions between CARMA1, BCL10, and MALT1 were lost. This failure in CBM assembly reduced inhibitor of kappa B alpha phosphorylation and diminished NF-κB-DNA binding. Finally, using a luciferase gene reporter assay, we show the intracellular domain of NOTCH1 can initiate robust NF-κB activity in stimulated T cells, even when NOTCH1 is excluded from the nucleus through modifications that restrict it to the cytoplasm or hold it tethered to the membrane. Collectively, these observations provide evidence that NOTCH1 may facilitate early events during T cell activation by nucleating the CBM complex and initiating NF-κB signaling.
- Published
- 2014
- Full Text
- View/download PDF
39. β-Catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T cells.
- Author
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Keerthivasan S, Aghajani K, Dose M, Molinero L, Khan MW, Venkateswaran V, Weber C, Emmanuel AO, Sun T, Bentrem DJ, Mulcahy M, Keshavarzian A, Ramos EM, Blatner N, Khazaie K, and Gounari F
- Subjects
- Animals, Binding Sites, CD4-Positive T-Lymphocytes immunology, Cell Line, Tumor, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic immunology, Cell Transformation, Neoplastic metabolism, Chromatin Assembly and Disassembly, Colitis genetics, Colitis immunology, Colitis pathology, Colon immunology, Colon pathology, Colonic Neoplasms genetics, Colonic Neoplasms immunology, Colonic Neoplasms pathology, DNA-Binding Proteins deficiency, DNA-Binding Proteins genetics, Disease Models, Animal, Gene Expression Regulation, Neoplastic, Genes, APC, Hepatocyte Nuclear Factor 1-alpha, Humans, Lymphocyte Activation, Lymphocytes, Tumor-Infiltrating immunology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nuclear Receptor Subfamily 1, Group F, Member 3 genetics, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, T Cell Transcription Factor 1 genetics, T Cell Transcription Factor 1 metabolism, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Th17 Cells immunology, Th17 Cells metabolism, Wnt Signaling Pathway, beta Catenin genetics, CD4-Positive T-Lymphocytes metabolism, Colitis metabolism, Colon metabolism, Colonic Neoplasms metabolism, Inflammation Mediators metabolism, Lymphocytes, Tumor-Infiltrating metabolism, beta Catenin metabolism
- Abstract
The density and type of lymphocytes that infiltrate colon tumors are predictive of the clinical outcome of colon cancer. High densities of T helper 17 (T(H)17) cells and inflammation predict poor outcome, whereas infiltration by T regulatory cells (Tregs) that naturally suppress inflammation is associated with longer patient survival. However, the role of Tregs in cancer remains controversial. We recently reported that Tregs in colon cancer patients can become proinflammatory and tumor-promoting. These properties were directly linked with their expression of RORγt (retinoic acid-related orphan receptor-γt), the signature transcription factor of T(H)17 cells. We report that Wnt/β-catenin signaling in T cells promotes expression of RORγt. Expression of β-catenin was elevated in T cells, including Tregs, of patients with colon cancer. Genetically engineered activation of β-catenin in mouse T cells resulted in enhanced chromatin accessibility in the proximity of T cell factor-1 (Tcf-1) binding sites genome-wide, induced expression of T(H)17 signature genes including RORγt, and promoted T(H)17-mediated inflammation. Strikingly, the mice had inflammation of small intestine and colon and developed lesions indistinguishable from colitis-induced cancer. Activation of β-catenin only in Tregs was sufficient to produce inflammation and initiate cancer. On the basis of these findings, we conclude that activation of Wnt/β-catenin signaling in effector T cells and/or Tregs is causatively linked with the imprinting of proinflammatory properties and the promotion of colon cancer.
- Published
- 2014
- Full Text
- View/download PDF
40. β-Catenin induces T-cell transformation by promoting genomic instability.
- Author
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Dose M, Emmanuel AO, Chaumeil J, Zhang J, Sun T, Germar K, Aghajani K, Davis EM, Keerthivasan S, Bredemeyer AL, Sleckman BP, Rosen ST, Skok JA, Le Beau MM, Georgopoulos K, and Gounari F
- Subjects
- Animals, Apoptosis, Base Sequence, Cell Survival, DNA Breaks, Double-Stranded, DNA Methylation, DNA Repair, Disease Models, Animal, Genes, RAG-1 genetics, Hepatocyte Nuclear Factor 1-alpha, Histones metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Molecular Sequence Data, Recombination, Genetic, T Cell Transcription Factor 1 metabolism, Thymocytes cytology, Translocation, Genetic, beta Catenin genetics, Genomic Instability, Lymphocyte Activation, Lymphoma genetics, T-Lymphocytes cytology, beta Catenin metabolism
- Abstract
Deregulated activation of β-catenin in cancer has been correlated with genomic instability. During thymocyte development, β-catenin activates transcription in partnership with T-cell-specific transcription factor 1 (Tcf-1). We previously reported that targeted activation of β-catenin in thymocytes (CAT mice) induces lymphomas that depend on recombination activating gene (RAG) and myelocytomatosis oncogene (Myc) activities. Here we show that these lymphomas have recurring Tcra/Myc translocations that resulted from illegitimate RAG recombination events and resembled oncogenic translocations previously described in human T-ALL. We therefore used the CAT animal model to obtain mechanistic insights into the transformation process. ChIP-seq analysis uncovered a link between Tcf-1 and RAG2 showing that the two proteins shared binding sites marked by trimethylated histone-3 lysine-4 (H3K4me3) throughout the genome, including near the translocation sites. Pretransformed CAT thymocytes had increased DNA damage at the translocating loci and showed altered repair of RAG-induced DNA double strand breaks. These cells were able to survive despite DNA damage because activated β-catenin promoted an antiapoptosis gene expression profile. Thus, activated β-catenin promotes genomic instability that leads to T-cell lymphomas as a consequence of altered double strand break repair and increased survival of thymocytes with damaged DNA.
- Published
- 2014
- Full Text
- View/download PDF
41. Generation of CD4CreER(T²) transgenic mice to study development of peripheral CD4-T-cells.
- Author
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Aghajani K, Keerthivasan S, Yu Y, and Gounari F
- Subjects
- Animals, CD4 Antigens metabolism, CD4-Positive T-Lymphocytes metabolism, Cell Differentiation, Gene Targeting methods, Genetic Engineering methods, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Integrases drug effects, Integrases genetics, Lymph Nodes cytology, Mice, Mice, Transgenic, Promoter Regions, Genetic, Spleen cytology, Tamoxifen pharmacology, Transcription, Genetic, CD4 Antigens genetics, CD4-Positive T-Lymphocytes cytology, Transgenes
- Abstract
After thymic emigration CD4-T-cells continue to differentiate into multiple effector and suppressor sublineages in peripheral lymphoid organs. In vivo analysis of peripheral CD4-T-cell differentiation has relied on animal models with targeted gene mutations. These are expressed either constitutively or conditionally after Cre mediated recombination. Available Cre transgenic strains to specifically target T-cells act at stages of thymocyte development that precede thymic selection. Tracing gene functions in CD4-T-cell development after thymic exit becomes complicated when the targeted gene is essential during thymic development. Other approaches to conditionally modify gene functions in peripheral T-cells involve infection of in vitro activated cells with Cre expressing lenti-, retro-, or adenoviruses, which precludes in vivo analyses. To study molecular mechanisms of peripheral CD4-T-cell differentiation in vivo and in vitro we generated transgenic mice expressing a tamoxifen inducible Cre recombinase (CreER(T2) ) under the control of the CD4 gene promoter. We show here that in CD4CreER(T2) mice Cre is inducibly and selectively activated in CD4-T-cells. Tamoxifen treatment both in vivo and in vitro results in efficient recombination of loci marked by LoxP sites. Moreover, this strain shows no abnormalities related to transgene insertion. Therefore it provides a valuable tool for studying gene function during differentiation of naïve peripheral CD4-T-cells into effector or suppressor sub-lineages., (Copyright © 2012 Wiley Periodicals, Inc.)
- Published
- 2012
- Full Text
- View/download PDF
42. Notch signaling regulates mouse and human Th17 differentiation.
- Author
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Keerthivasan S, Suleiman R, Lawlor R, Roderick J, Bates T, Minter L, Anguita J, Juncadella I, Nickoloff BJ, Le Poole IC, Miele L, and Osborne BA
- Subjects
- Animals, Cells, Cultured, Cytokines antagonists & inhibitors, Cytokines physiology, Down-Regulation immunology, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental pathology, Encephalomyelitis, Autoimmune, Experimental therapy, HEK293 Cells, Humans, Interleukin-17 antagonists & inhibitors, Interleukin-17 metabolism, Mice, Mice, Inbred C57BL, Multiple Sclerosis immunology, Multiple Sclerosis pathology, Multiple Sclerosis therapy, Th17 Cells metabolism, Th17 Cells pathology, Cell Differentiation immunology, Receptor, Notch1 physiology, Signal Transduction immunology, Th17 Cells immunology
- Abstract
Th17 cells are known to play a critical role in adaptive immune responses to several important extracellular pathogens. Additionally, Th17 cells are implicated in the pathogenesis of several autoimmune and inflammatory disorders as well as in cancer. Therefore, it is essential to understand the mechanisms that regulate Th17 differentiation. Notch signaling is known to be important at several stages of T cell development and differentiation. In this study, we report that Notch1 is activated in both mouse and human in vitro-polarized Th17 cells and that blockade of Notch signaling significantly downregulates the production of Th17-associated cytokines, suggesting an intrinsic requirement for Notch during Th17 differentiation in both species. We also present evidence, using promoter reporter assays, knockdown studies, as well as chromatin immunoprecipitation, that IL-17 and retinoic acid-related orphan receptor γt are direct transcriptional targets of Notch signaling in Th17 cells. Finally, in vivo inhibition of Notch signaling reduced IL-17 production and Th17-mediated disease progression in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Thus, this study highlights the importance of Notch signaling in Th17 differentiation and indicates that selective targeted therapy against Notch may be an important tool to treat autoimmune disorders, including multiple sclerosis.
- Published
- 2011
- Full Text
- View/download PDF
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