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1. High-throughput RNA isoform sequencing using programmed cDNA concatenation

Author

Al’Khafaji, Aziz M., Smith, Jonathan T., Garimella, Kiran V., Babadi, Mehrtash, Popic, Victoria, Sade-Feldman, Moshe, Gatzen, Michael, Sarkizova, Siranush, Schwartz, Marc A., Blaum, Emily M., Day, Allyson, Costello, Maura, Bowers, Tera, Gabriel, Stacey, Banks, Eric, Philippakis, Anthony A., Boland, Genevieve M., Blainey, Paul C., and Hacohen, Nir

Published
2024
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2. Unsupervised Protein-Ligand Binding Energy Prediction via Neural Euler's Rotation Equation

Author

Jin, Wengong, Sarkizova, Siranush, Chen, Xun, Hacohen, Nir, and Uhler, Caroline

Subjects
Quantitative Biology - Biomolecules, Computer Science - Machine Learning
Abstract

Protein-ligand binding prediction is a fundamental problem in AI-driven drug discovery. Prior work focused on supervised learning methods using a large set of binding affinity data for small molecules, but it is hard to apply the same strategy to other drug classes like antibodies as labelled data is limited. In this paper, we explore unsupervised approaches and reformulate binding energy prediction as a generative modeling task. Specifically, we train an energy-based model on a set of unlabelled protein-ligand complexes using SE(3) denoising score matching and interpret its log-likelihood as binding affinity. Our key contribution is a new equivariant rotation prediction network called Neural Euler's Rotation Equations (NERE) for SE(3) score matching. It predicts a rotation by modeling the force and torque between protein and ligand atoms, where the force is defined as the gradient of an energy function with respect to atom coordinates. We evaluate NERE on protein-ligand and antibody-antigen binding affinity prediction benchmarks. Our model outperforms all unsupervised baselines (physics-based and statistical potentials) and matches supervised learning methods in the antibody case.

Published
2023

3. Spatially organized multicellular immune hubs in human colorectal cancer.

Author

Pelka, Karin, Hofree, Matan, Chen, Jonathan, Sarkizova, Siranush, Pirl, Joshua, Jorgji, Vjola, Bejnood, Alborz, Dionne, Danielle, Ge, William, Xu, Katherine, Chao, Sherry, Zollinger, Daniel, Lieb, David, Reeves, Jason, Fuhrman, Christopher, Hoang, Margaret, Delorey, Toni, Nguyen, Lan, Waldman, Julia, Klapholz, Max, Wakiro, Isaac, Cohen, Ofir, Albers, Julian, Smillie, Christopher, Cuoco, Michael, Wu, Jingyi, Su, Mei-Ju, Yeung, Jason, Vijaykumar, Brinda, Magnuson, Angela, Asinovski, Natasha, Moll, Tabea, Goder-Reiser, Max, Applebaum, Anise, Brais, Lauren, DelloStritto, Laura, Denning, Sarah, Phillips, Susannah, Hill, Emma, Meehan, Julia, Frederick, Dennie, Sharova, Tatyana, Kanodia, Abhay, Todres, Ellen, Jané-Valbuena, Judit, Biton, Moshe, Izar, Benjamin, Lambden, Conner, Clancy, Thomas, Bleday, Ronald, Melnitchouk, Nelya, Irani, Jennifer, Kunitake, Hiroko, Berger, David, Srivastava, Amitabh, Hornick, Jason, Ogino, Shuji, Rotem, Asaf, Vigneau, Sébastien, Johnson, Bruce, Corcoran, Ryan, Sharpe, Arlene, Kuchroo, Vijay, Ng, Kimmie, Giannakis, Marios, Nieman, Linda, Boland, Genevieve, Aguirre, Andrew, Anderson, Ana, Rozenblatt-Rosen, Orit, Regev, Aviv, and Hacohen, Nir

Subjects
MSI, MSS, anti-tumor immunity, cell-cell interactions, colorectal cancer, mismatch repair-deficient, mismatch repair-proficient, scRNA-seq, spatial, tumor atlas, Bone Morphogenetic Proteins, Cancer-Associated Fibroblasts, Cell Compartmentation, Cell Line, Tumor, Chemokines, Cohort Studies, Colorectal Neoplasms, DNA Mismatch Repair, Endothelial Cells, Gene Expression Regulation, Neoplastic, Humans, Immunity, Inflammation, Monocytes, Myeloid Cells, Neutrophils, Stromal Cells, T-Lymphocytes, Transcription, Genetic
Abstract

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.

Published
2021

4. The HLA-II immunopeptidome of SARS-CoV-2

Author

Weingarten-Gabbay, Shira, Chen, Da-Yuan, Sarkizova, Siranush, Taylor, Hannah B., Gentili, Matteo, Hernandez, Gabrielle M., Pearlman, Leah R., Bauer, Matthew R., Rice, Charles M., Clauser, Karl R., Hacohen, Nir, Carr, Steven A., Abelin, Jennifer G., Saeed, Mohsan, and Sabeti, Pardis C.

Published
2024
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5. Unannotated proteins expand the MHC-I-restricted immunopeptidome in cancer

Author

Ouspenskaia, Tamara, Law, Travis, Clauser, Karl R., Klaeger, Susan, Sarkizova, Siranush, Aguet, François, Li, Bo, Christian, Elena, Knisbacher, Binyamin A., Le, Phuong M., Hartigan, Christina R., Keshishian, Hasmik, Apffel, Annie, Oliveira, Giacomo, Zhang, Wandi, Chen, Sarah, Chow, Yuen Ting, Ji, Zhe, Jungreis, Irwin, Shukla, Sachet A., Justesen, Sune, Bachireddy, Pavan, Kellis, Manolis, Getz, Gad, Hacohen, Nir, Keskin, Derin B., Carr, Steven A., Wu, Catherine J., and Regev, Aviv

Published
2022
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6. Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs

Author

Lavin-Parsons, Kendall, Parry, Blair, Lilley, Brendan, Lodenstein, Carl, McKaig, Brenna, Charland, Nicole, Khanna, Hargun, Margolin, Justin, Gonye, Anna, Gushterova, Irena, Lasalle, Tom, Sharma, Nihaarika, Russo, Brian C., Rojas-Lopez, Maricarmen, Sade-Feldman, Moshe, Manakongtreecheep, Kasidet, Tantivit, Jessica, Fisher Thomas, Molly, Weingarten-Gabbay, Shira, Klaeger, Susan, Sarkizova, Siranush, Pearlman, Leah R., Chen, Da-Yuan, Gallagher, Kathleen M.E., Bauer, Matthew R., Taylor, Hannah B., Dunn, W. Augustine, Tarr, Christina, Sidney, John, Rachimi, Suzanna, Conway, Hasahn L., Katsis, Katelin, Wang, Yuntong, Leistritz-Edwards, Del, Durkin, Melissa R., Tomkins-Tinch, Christopher H., Finkel, Yaara, Nachshon, Aharon, Gentili, Matteo, Rivera, Keith D., Carulli, Isabel P., Chea, Vipheaviny A., Chandrashekar, Abishek, Bozkus, Cansu Cimen, Carrington, Mary, Bhardwaj, Nina, Barouch, Dan H., Sette, Alessandro, Maus, Marcela V., Rice, Charles M., Clauser, Karl R., Keskin, Derin B., Pregibon, Daniel C., Hacohen, Nir, Carr, Steven A., Abelin, Jennifer G., Saeed, Mohsan, and Sabeti, Pardis C.

Published
2021
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7. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors.

Author

Fletcher, James, Griesbeck, Morgane, Butler, Andrew, Zheng, Shiwei, Lazo, Suzan, Jardine, Laura, Dixon, David, Stephenson, Emily, Nilsson, Emil, Grundberg, Ida, McDonald, David, Filby, Andrew, Li, Weibo, De Jager, Philip, Rozenblatt-Rosen, Orit, Lane, Andrew, Haniffa, Muzlifah, Regev, Aviv, Hacohen, Nir, Villani, Alexandra-Chloé, Satija, Rahul, Reynolds, Gary, Sarkizova, Siranush, and Shekhar, Karthik

Subjects
Adult, Antigen Presentation, Classification, Dendritic Cells, Female, Gene Expression Profiling, Humans, Lymphocyte Activation, Male, Monitoring, Immunologic, Monocytes, Neoplasms, Sequence Analysis, RNA, Single-Cell Analysis, T-Lymphocytes, Transcriptome, Young Adult
Abstract

Dendritic cells (DCs) and monocytes play a central role in pathogen sensing, phagocytosis, and antigen presentation and consist of multiple specialized subtypes. However, their identities and interrelationships are not fully understood. Using unbiased single-cell RNA sequencing (RNA-seq) of ~2400 cells, we identified six human DCs and four monocyte subtypes in human blood. Our study reveals a new DC subset that shares properties with plasmacytoid DCs (pDCs) but potently activates T cells, thus redefining pDCs; a new subdivision within the CD1C+ subset of DCs; the relationship between blastic plasmacytoid DC neoplasia cells and healthy DCs; and circulating progenitor of conventional DCs (cDCs). Our revised taxonomy will enable more accurate functional and developmental analyses as well as immune monitoring in health and disease.

Published
2017

8. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors

Author

Villani, Alexandra-Chloé, Satija, Rahul, Reynolds, Gary, Sarkizova, Siranush, Shekhar, Karthik, Fletcher, James, Griesbeck, Morgane, Butler, Andrew, Zheng, Shiwei, Lazo, Suzan, Jardine, Laura, Dixon, David, Stephenson, Emily, Nilsson, Emil, Grundberg, Ida, McDonald, David, Filby, Andrew, Li, Weibo, De Jager, Philip L, Rozenblatt-Rosen, Orit, Lane, Andrew A, Haniffa, Muzlifah, Regev, Aviv, and Hacohen, Nir

Subjects
Neurosciences, Stem Cell Research, Prevention, Vaccine Related, Clinical Research, Genetics, 1.1 Normal biological development and functioning, Underpinning research, Inflammatory and immune system, Good Health and Well Being, Adult, Antigen Presentation, Classification, Dendritic Cells, Female, Gene Expression Profiling, Humans, Lymphocyte Activation, Male, Monitoring, Immunologic, Monocytes, Neoplasms, Sequence Analysis, RNA, Single-Cell Analysis, T-Lymphocytes, Transcriptome, Young Adult, General Science & Technology
Abstract

Dendritic cells (DCs) and monocytes play a central role in pathogen sensing, phagocytosis, and antigen presentation and consist of multiple specialized subtypes. However, their identities and interrelationships are not fully understood. Using unbiased single-cell RNA sequencing (RNA-seq) of ~2400 cells, we identified six human DCs and four monocyte subtypes in human blood. Our study reveals a new DC subset that shares properties with plasmacytoid DCs (pDCs) but potently activates T cells, thus redefining pDCs; a new subdivision within the CD1C+ subset of DCs; the relationship between blastic plasmacytoid DC neoplasia cells and healthy DCs; and circulating progenitor of conventional DCs (cDCs). Our revised taxonomy will enable more accurate functional and developmental analyses as well as immune monitoring in health and disease.

Published
2017

9. Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma

Author

Hu, Zhuting, Leet, Donna E., Allesøe, Rosa L., Oliveira, Giacomo, Li, Shuqiang, Luoma, Adrienne M., Liu, Jinyan, Forman, Juliet, Huang, Teddy, Iorgulescu, J. Bryan, Holden, Rebecca, Sarkizova, Siranush, Gohil, Satyen H., Redd, Robert A., Sun, Jing, Elagina, Liudmila, Giobbie-Hurder, Anita, Zhang, Wandi, Peter, Lauren, Ciantra, Zoe, Rodig, Scott, Olive, Oriol, Shetty, Keerthi, Pyrdol, Jason, Uduman, Mohamed, Lee, Patrick C., Bachireddy, Pavan, Buchbinder, Elizabeth I., Yoon, Charles H., Neuberg, Donna, Pentelute, Bradley L., Hacohen, Nir, Livak, Kenneth J., Shukla, Sachet A., Olsen, Lars Rønn, Barouch, Dan H., Wucherpfennig, Kai W., Fritsch, Edward F., Keskin, Derin B., Wu, Catherine J., and Ott, Patrick A.

Published
2021
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10. A large peptidome dataset improves HLA class I epitope prediction across most of the human population

Author

Sarkizova, Siranush, Klaeger, Susan, Le, Phuong M., Li, Letitia W., Oliveira, Giacomo, Keshishian, Hasmik, Hartigan, Christina R., Zhang, Wandi, Braun, David A., Ligon, Keith L., Bachireddy, Pavan, Zervantonakis, Ioannis K., Rosenbluth, Jennifer M., Ouspenskaia, Tamara, Law, Travis, Justesen, Sune, Stevens, Jonathan, Lane, William J., Eisenhaure, Thomas, Lan Zhang, Guang, Clauser, Karl R., Hacohen, Nir, Carr, Steven A., Wu, Catherine J., and Keskin, Derin B.

Published
2020
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11. High-throughput RNA isoform sequencing using programmed cDNA concatenation.

Author

Al'Khafaji, Aziz M., Smith, Jonathan T., Garimella, Kiran V., Babadi, Mehrtash, Popic, Victoria, Sade-Feldman, Moshe, Gatzen, Michael, Sarkizova, Siranush, Schwartz, Marc A., Blaum, Emily M., Day, Allyson, Costello, Maura, Bowers, Tera, Gabriel, Stacey, Banks, Eric, Philippakis, Anthony A., Boland, Genevieve M., Blainey, Paul C., and Hacohen, Nir

Abstract

Full-length RNA-sequencing methods using long-read technologies can capture complete transcript isoforms, but their throughput is limited. We introduce multiplexed arrays isoform sequencing (MAS-ISO-seq), a technique for programmably concatenating complementary DNAs (cDNAs) into molecules optimal for long-read sequencing, increasing the throughput >15-fold to nearly 40 million cDNA reads per run on the Sequel IIe sequencer. When applied to single-cell RNA sequencing of tumor-infiltrating T cells, MAS-ISO-seq demonstrated a 12- to 32-fold increase in the discovery of differentially spliced genes. Programmable concatenation of cDNA molecules increases the throughput of PacBio sequencing about 15-fold. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Abstract PR015: Tumor-specific immunity generated by a personalized neoantigen vaccination incorporating locally delivered ipilimumab in renal cell carcinoma

Author

Braun, David A., primary, Keskin, Derin B., additional, Shukla, Sachet A., additional, McGregor, Bradley A., additional, Schindler, Nicholas R., additional, Blass, Eryn, additional, Klaeger, Susan, additional, Pomerance, Lucas, additional, Sarkizova, Siranush, additional, Li, Shuqiang, additional, Southard, Jackson, additional, Moranzoni, Giorgia, additional, Pedersen, Christina B., additional, Liu, Yiwen, additional, Chang, Steven L., additional, Hirsch, Michelle S., additional, LeBoeuf, Nicole R., additional, Mossanen, Matthew, additional, Chea, Vipheaviny, additional, Carulli, Isabel, additional, Olive, Oriol, additional, Mehndiratta, Ambica, additional, Greenslade, Haley, additional, Oliveira, Giacomo, additional, Iorgulescu, J. Bryan, additional, Signoretti, Sabina, additional, Aster, Jon C., additional, Elagina, Liudmila, additional, Leshchiner, Ignaty, additional, Getz, Gad, additional, Harden, Maegan, additional, Gabriel, Stacey, additional, Olsen, Lars R., additional, Neuberg, Donna S., additional, Fritsch, Edward F., additional, Hacohen, Nir, additional, Livak, Kenneth J., additional, Carr, Steven, additional, Ott, Patrick A., additional, Wu, Catherine J., additional, and Choueiri, Toni K., additional

Published
2023
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13. Abstract A013: Tumor-specific immunity generated by a personalized neoantigen vaccination incorporating locally delivered ipilimumab in renal cell carcinoma

Author

Braun, David A., primary, Keskin, Derin B., additional, Shukla, Sachet A., additional, McGregor, Bradley A., additional, Schindler, Nicholas R., additional, Blass, Eryn, additional, Klaeger, Susan, additional, Pomerance, Lucas, additional, Sarkizova, Siranush, additional, Li, Shuqiang, additional, Southard, Jackson, additional, Moranzoni, Giorgia, additional, Pedersen, Christina B., additional, Liu, Yiwen, additional, Chang, Steven L., additional, Hirsch, Michelle S., additional, LeBoeuf, Nicole R., additional, Mossanen, Matthew, additional, Chea, Vipheaviny, additional, Carulli, Isabel, additional, Olive, Oriol, additional, Mehndiratta, Ambica, additional, Greenslade, Haley, additional, Oliveira, Giacomo, additional, Iorgulescu, J. Bryan, additional, Signoretti, Sabina, additional, Aster, Jon C., additional, Elagina, Liudmila, additional, Leshchiner, Ignaty, additional, Getz, Gad, additional, Harden, Maegan, additional, Gabriel, Stacey, additional, Olsen, Lars R., additional, Neuberg, Donna S., additional, Fritsch, Edward F., additional, Hacohen, Nir, additional, Livak, Kenneth J., additional, Carr, Steven, additional, Ott, Patrick A., additional, Wu, Catherine J., additional, and Choueiri, Toni K., additional

Published
2023
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15. The HLA-II immunopeptidome of SARS-CoV-2

Author

Weingarten-Gabbay, Shira, Chen, Da-Yuan, Sarkizova, Siranush, Taylor, Hannah B., Gentili, Matteo, Pearlman, Leah R., Bauer, Matthew R., Rice, Charles M., Clauser, Karl R., Hacohen, Nir, Carr, Steven A., Abelin, Jennifer G., Saeed, Mohsan, and Sabeti, Pardis C.

Subjects
Article
Abstract

Targeted synthetic vaccines have the potential to transform our response to viral outbreaks; yet the design of these vaccines requires a comprehensive knowledge of viral immunogens, including T-cell epitopes. Having previously mapped the SARS-CoV-2 HLA-I landscape, here we report viral peptides that are naturally processed and loaded onto HLA-II complexes in infected cells. We identified over 500 unique viral peptides from canonical proteins, as well as from overlapping internal open reading frames (ORFs), revealing, for the first time, the contribution of internal ORFs to the HLA-II peptide repertoire. Most HLA-II peptides co-localized with the known CD4+ T cell epitopes in COVID-19 patients. We also observed that two reported immunodominant regions in the SARS-CoV-2 membrane protein are formed at the level of HLA-II presentation. Overall, our analyses show that HLA-I and HLA-II pathways target distinct viral proteins, with the structural proteins accounting for most of the HLA-II peptidome and non-structural and non-canonical proteins accounting for the majority of the HLA-I peptidome. These findings highlight the need for a vaccine design that incorporates multiple viral elements harboring CD4+ and CD8+ T cell epitopes to maximize the vaccine effectiveness.

Published
2023

16. Systematic Identification of Autosomal and Y-Encoded Minor Histocompatibility Antigens Reveals Predictors of Chronic GvHD and Candidate Gvl Targets

Author

Cieri, Nicoletta, primary, Hookeri, Nidhi, additional, Stromhaug, Kari, additional, Stevens, Jonathan, additional, Kooshesh, Kameron, additional, Ji, Helen, additional, Klaeger, Susan, additional, Clauser, Karl R., additional, Sarkizova, Siranush, additional, Braun, David A., additional, Penter, Livius, additional, Oliveira, Giacomo, additional, Kim, Haesook T., additional, Lane, William J., additional, Li, Shuqiang, additional, Livak, Kenneth J., additional, Ho, Vincent T., additional, Ritz, Jerome, additional, Soiffer, Robert J., additional, Keskin, Derin B., additional, Stewart, Chip, additional, Gusev, Alexander, additional, Getz, Gad, additional, and Wu, Catherine J., additional

Published
2023
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17. Systematic Identification of Autosomal and Y-Encoded Minor Histocompatibility Antigens Reveals Predictors of Chronic Gvhd and Candidate GVL Targets

Author

Cieri, Nicoletta, primary, Hookeri, Nidhi, additional, Stromhaug, Kari, additional, Stevens, Jonathan, additional, Kooshesh, Kameron, additional, Klaeger, Susan, additional, Clauser, Karl R., additional, Sarkizova, Siranush, additional, Braun, David A., additional, Penter, Livius, additional, Oliveira, Giacomo, additional, Kim, Haesook T., additional, Lane, William J., additional, Li, Shuqiang, additional, Livak, Kenneth J., additional, Ho, Vincent T., additional, Ritz, Jerome, additional, Soiffer, Robert J., additional, Keskin, Derin B., additional, Stewart, Chip, additional, Gusev, Alexander, additional, Getz, Gad, additional, and Wu, Catherine J., additional

Published
2022
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20. Virally mediated mechanisms of HLA class I loss in Merkel cell carcinoma and implications for viral epitope presentation

Author

Keskin, Derin B., primary, Lee, Patrick C., additional, Klaeger, Susan, additional, Le, Phuong M., additional, Korthauer, Keegan, additional, Cheng, Jingwei, additional, Ananthapadmanabhan, Varsha, additional, Frost, Thomas C., additional, Iorgulescu, J. Bryan, additional, Lemvigh, Camilla K., additional, Pedersen, Christina B., additional, Sarkizova, Siranush, additional, Li, Shuqiang, additional, Liu, Xiaoxi, additional, Doherty, Laura M., additional, Neuberg, Donna, additional, Zhang, Guanglan, additional, Olsen, Lars R., additional, Thakuria, Manisha, additional, Rodig, Scott J., additional, Clauser, Karl R., additional, Starrett, Gabriel J., additional, Doench, John G., additional, Buhrlage, Sara J., additional, Carr, Steven A., additional, DeCaprio, James A., additional, and Wu, Catherine J., additional

Published
2022
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21. Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma

Author

Lee, Patrick C., primary, Klaeger, Susan, additional, Le, Phuong M., additional, Korthauer, Keegan, additional, Cheng, Jingwei, additional, Ananthapadmanabhan, Varsha, additional, Frost, Thomas C., additional, Stevens, Jonathan D., additional, Wong, Alan Y.L., additional, Iorgulescu, J. Bryan, additional, Tarren, Anna Y., additional, Chea, Vipheaviny A., additional, Carulli, Isabel P., additional, Lemvigh, Camilla K., additional, Pedersen, Christina B., additional, Gartin, Ashley K., additional, Sarkizova, Siranush, additional, Wright, Kyle T., additional, Li, Letitia W., additional, Nomburg, Jason, additional, Li, Shuqiang, additional, Huang, Teddy, additional, Liu, Xiaoxi, additional, Pomerance, Lucas, additional, Doherty, Laura M., additional, Apffel, Annie M., additional, Wallace, Luke J., additional, Rachimi, Suzanna, additional, Felt, Kristen D., additional, Wolff, Jacquelyn O., additional, Witten, Elizabeth, additional, Zhang, Wandi, additional, Neuberg, Donna, additional, Lane, William J., additional, Zhang, Guanglan, additional, Olsen, Lars R., additional, Thakuria, Manisha, additional, Rodig, Scott J., additional, Clauser, Karl R., additional, Starrett, Gabriel J., additional, Doench, John G., additional, Buhrlage, Sara J., additional, Carr, Steven A., additional, DeCaprio, James A., additional, Wu, Catherine J., additional, and Keskin, Derin B., additional

Published
2022
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22. Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma

Author

Lee, Patrick C., Klaeger, Susan, Le, Phuong M., Korthauer, Keegan, Cheng, Jingwei, Ananthapadmanabhan, Varsha, Frost, Thomas C., Stevens, Jonathan D., Wong, Alan Y.L., Iorgulescu, J. Bryan, Tarren, Anna Y., Chea, Vipheaviny A., Carulli, Isabel P., Lemvigh, Camilla K., Pedersen, Christina B., Gartin, Ashley K., Sarkizova, Siranush, Wright, Kyle T., Li, Letitia W., Nomburg, Jason, Li, Shuqiang, Huang, Teddy, Liu, Xiaoxi, Pomerance, Lucas, Doherty, Laura M., Apffel, Annie M., Wallace, Luke J., Rachimi, Suzanna, Felt, Kristen D., Wolff, Jacquelyn O., Witten, Elizabeth, Zhang, Wandi, Neuberg, Donna, Lane, William J., Zhang, Guanglan, Olsen, Lars R., Thakuria, Manisha, Rodig, Scott J., Clauser, Karl R., Starrett, Gabriel J., Doench, John G., Buhrlage, Sara J., Carr, Steven A., DeCaprio, James A., Wu, Catherine J., Keskin, Derin B., Lee, Patrick C., Klaeger, Susan, Le, Phuong M., Korthauer, Keegan, Cheng, Jingwei, Ananthapadmanabhan, Varsha, Frost, Thomas C., Stevens, Jonathan D., Wong, Alan Y.L., Iorgulescu, J. Bryan, Tarren, Anna Y., Chea, Vipheaviny A., Carulli, Isabel P., Lemvigh, Camilla K., Pedersen, Christina B., Gartin, Ashley K., Sarkizova, Siranush, Wright, Kyle T., Li, Letitia W., Nomburg, Jason, Li, Shuqiang, Huang, Teddy, Liu, Xiaoxi, Pomerance, Lucas, Doherty, Laura M., Apffel, Annie M., Wallace, Luke J., Rachimi, Suzanna, Felt, Kristen D., Wolff, Jacquelyn O., Witten, Elizabeth, Zhang, Wandi, Neuberg, Donna, Lane, William J., Zhang, Guanglan, Olsen, Lars R., Thakuria, Manisha, Rodig, Scott J., Clauser, Karl R., Starrett, Gabriel J., Doench, John G., Buhrlage, Sara J., Carr, Steven A., DeCaprio, James A., Wu, Catherine J., and Keskin, Derin B.

Abstract

Cancers avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I antigen presentation. Merkel cell carcinoma (MCC) is an aggressive, HLA-I–low, neuroendocrine carcinoma of the skin often caused by the Merkel cell polyomavirus (MCPyV). Through the characterization of 11 newly generated MCC patient-derived cell lines, we identified transcriptional suppression of several class I antigen presentation genes. To systematically identify regulators of HLA-I loss in MCC, we performed parallel, genome-scale, gain- and loss-of-function screens in a patient-derived MCPyV-positive cell line and identified MYCL and the non-canonical Polycomb repressive complex 1.1 (PRC1.1) as HLA-I repressors. We observed physical interaction of MYCL with the MCPyV small T viral antigen, supporting a mechanism of virally mediated HLA-I suppression. We further identify the PRC1.1 component USP7 as a pharmacologic target to restore HLA-I expression in MCC.

Published
2022

24. Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps

Author

Chen, Bob, primary, Scurrah, Cherie’ R., additional, McKinley, Eliot T., additional, Simmons, Alan J., additional, Ramirez-Solano, Marisol A., additional, Zhu, Xiangzhu, additional, Markham, Nicholas O., additional, Heiser, Cody N., additional, Vega, Paige N., additional, Rolong, Andrea, additional, Kim, Hyeyon, additional, Sheng, Quanhu, additional, Drewes, Julia L., additional, Zhou, Yuan, additional, Southard-Smith, Austin N., additional, Xu, Yanwen, additional, Ro, James, additional, Jones, Angela L., additional, Revetta, Frank, additional, Berry, Lynne D., additional, Niitsu, Hiroaki, additional, Islam, Mirazul, additional, Pelka, Karin, additional, Hofree, Matan, additional, Chen, Jonathan H., additional, Sarkizova, Siranush, additional, Ng, Kimmie, additional, Giannakis, Marios, additional, Boland, Genevieve M., additional, Aguirre, Andrew J., additional, Anderson, Ana C., additional, Rozenblatt-Rosen, Orit, additional, Regev, Aviv, additional, Hacohen, Nir, additional, Kawasaki, Kenta, additional, Sato, Toshiro, additional, Goettel, Jeremy A., additional, Grady, William M., additional, Zheng, Wei, additional, Washington, M. Kay, additional, Cai, Qiuyin, additional, Sears, Cynthia L., additional, Goldenring, James R., additional, Franklin, Jeffrey L., additional, Su, Timothy, additional, Huh, Won Jae, additional, Vandekar, Simon, additional, Roland, Joseph T., additional, Liu, Qi, additional, Coffey, Robert J., additional, Shrubsole, Martha J., additional, and Lau, Ken S., additional

Published
2021
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25. Unannotated proteins expand the MHC-I-restricted immunopeptidome in cancer

Author

Ouspenskaia, Tamara, primary, Law, Travis, additional, Clauser, Karl R., additional, Klaeger, Susan, additional, Sarkizova, Siranush, additional, Aguet, François, additional, Li, Bo, additional, Christian, Elena, additional, Knisbacher, Binyamin A., additional, Le, Phuong M., additional, Hartigan, Christina R., additional, Keshishian, Hasmik, additional, Apffel, Annie, additional, Oliveira, Giacomo, additional, Zhang, Wandi, additional, Chen, Sarah, additional, Chow, Yuen Ting, additional, Ji, Zhe, additional, Jungreis, Irwin, additional, Shukla, Sachet A., additional, Justesen, Sune, additional, Bachireddy, Pavan, additional, Kellis, Manolis, additional, Getz, Gad, additional, Hacohen, Nir, additional, Keskin, Derin B., additional, Carr, Steven A., additional, Wu, Catherine J., additional, and Regev, Aviv, additional

Published
2021
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26. Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs

Author

Weingarten-Gabbay, Shira, primary, Klaeger, Susan, additional, Sarkizova, Siranush, additional, Pearlman, Leah R., additional, Chen, Da-Yuan, additional, Gallagher, Kathleen M.E., additional, Bauer, Matthew R., additional, Taylor, Hannah B., additional, Dunn, W. Augustine, additional, Tarr, Christina, additional, Sidney, John, additional, Rachimi, Suzanna, additional, Conway, Hasahn L., additional, Katsis, Katelin, additional, Wang, Yuntong, additional, Leistritz-Edwards, Del, additional, Durkin, Melissa R., additional, Tomkins-Tinch, Christopher H., additional, Finkel, Yaara, additional, Nachshon, Aharon, additional, Gentili, Matteo, additional, Rivera, Keith D., additional, Carulli, Isabel P., additional, Chea, Vipheaviny A., additional, Chandrashekar, Abishek, additional, Bozkus, Cansu Cimen, additional, Carrington, Mary, additional, Bhardwaj, Nina, additional, Barouch, Dan H., additional, Sette, Alessandro, additional, Maus, Marcela V., additional, Rice, Charles M., additional, Clauser, Karl R., additional, Keskin, Derin B., additional, Pregibon, Daniel C., additional, Hacohen, Nir, additional, Carr, Steven A., additional, Abelin, Jennifer G., additional, Saeed, Mohsan, additional, Sabeti, Pardis C., additional, Lavin-Parsons, Kendall, additional, Parry, Blair, additional, Lilley, Brendan, additional, Lodenstein, Carl, additional, McKaig, Brenna, additional, Charland, Nicole, additional, Khanna, Hargun, additional, Margolin, Justin, additional, Gonye, Anna, additional, Gushterova, Irena, additional, Lasalle, Tom, additional, Sharma, Nihaarika, additional, Russo, Brian C., additional, Rojas-Lopez, Maricarmen, additional, Sade-Feldman, Moshe, additional, Manakongtreecheep, Kasidet, additional, Tantivit, Jessica, additional, and Fisher Thomas, Molly, additional

Published
2021
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27. Cumulus provides cloud-based data analysis for large-scale single-cell and single-nucleus RNA-seq

Author

Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology. Department of Biology, Howard Hughes Medical Institute, Li, Bo, Gould, Joshua, Yang, Yiming, Sarkizova, Siranush, Tabaka, Marcin, Ashenberg, Orr, Rosen, Yanay, Slyper, Michal, Kowalczyk, Monika S, Villani, Alexandra-Chloé, Tickle, Timothy, Hacohen, Nir, Rozenblatt-Rosen, Orit, Regev, Aviv, Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology. Department of Biology, Howard Hughes Medical Institute, Li, Bo, Gould, Joshua, Yang, Yiming, Sarkizova, Siranush, Tabaka, Marcin, Ashenberg, Orr, Rosen, Yanay, Slyper, Michal, Kowalczyk, Monika S, Villani, Alexandra-Chloé, Tickle, Timothy, Hacohen, Nir, Rozenblatt-Rosen, Orit, and Regev, Aviv

Abstract

© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Massively parallel single-cell and single-nucleus RNA sequencing has opened the way to systematic tissue atlases in health and disease, but as the scale of data generation is growing, so is the need for computational pipelines for scaled analysis. Here we developed Cumulus—a cloud-based framework for analyzing large-scale single-cell and single-nucleus RNA sequencing datasets. Cumulus combines the power of cloud computing with improvements in algorithm and implementation to achieve high scalability, low cost, user-friendliness and integrated support for a comprehensive set of features. We benchmark Cumulus on the Human Cell Atlas Census of Immune Cells dataset of bone marrow cells and show that it substantially improves efficiency over conventional frameworks, while maintaining or improving the quality of results, enabling large-scale studies.

Published
2021

28. ERAP2 Increases the Abundance of a Peptide Submotif Highly Selective for the Birdshot Uveitis-Associated HLA-A29

Author

MS Oogheelkunde, Infection & Immunity, Genetica Sectie Genoomdiagnostiek, Cancer, Venema, Wouter J, Hiddingh, Sanne, de Boer, Joke H, Claas, Frans H J, Mulder, Arend, den Hollander, Anneke I, Stratikos, Efstratios, Sarkizova, Siranush, van der Veken, Lars T, Janssen, George M C, van Veelen, Peter A, Kuiper, Jonas J W, MS Oogheelkunde, Infection & Immunity, Genetica Sectie Genoomdiagnostiek, Cancer, Venema, Wouter J, Hiddingh, Sanne, de Boer, Joke H, Claas, Frans H J, Mulder, Arend, den Hollander, Anneke I, Stratikos, Efstratios, Sarkizova, Siranush, van der Veken, Lars T, Janssen, George M C, van Veelen, Peter A, and Kuiper, Jonas J W

Published
2021

29. ERAP2 Increases the Abundance of a Peptide Submotif Highly Selective for the Birdshot Uveitis-Associated HLA-A29

Author

Venema, Wouter J., primary, Hiddingh, Sanne, additional, de Boer, Joke H., additional, Claas, Frans H. J., additional, Mulder, Arend, additional, den Hollander, Anneke I., additional, Stratikos, Efstratios, additional, Sarkizova, Siranush, additional, van der Veken, Lars T., additional, Janssen, George M. C., additional, van Veelen, Peter A., additional, and Kuiper, Jonas J. W., additional

Published
2021
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30. Optimized Liquid and Gas Phase Fractionation Increases HLA-Peptidome Coverage for Primary Cell and Tissue Samples

Author

Klaeger, Susan, primary, Apffel, Annie, additional, Clauser, Karl R., additional, Sarkizova, Siranush, additional, Oliveira, Giacomo, additional, Rachimi, Suzanna, additional, Le, Phuong M., additional, Tarren, Anna, additional, Chea, Vipheaviny, additional, Abelin, Jennifer G., additional, Braun, David A., additional, Ott, Patrick A., additional, Keshishian, Hasmik, additional, Hacohen, Nir, additional, Keskin, Derin B., additional, Wu, Catherine J., additional, and Carr, Steven A., additional

Published
2021
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32. 35 - Systematic Identification of Autosomal and Y-Encoded Minor Histocompatibility Antigens Reveals Predictors of Chronic GvHD and Candidate Gvl Targets

Author

Cieri, Nicoletta, Hookeri, Nidhi, Stromhaug, Kari, Stevens, Jonathan, Kooshesh, Kameron, Ji, Helen, Klaeger, Susan, Clauser, Karl R., Sarkizova, Siranush, Braun, David A., Penter, Livius, Oliveira, Giacomo, Kim, Haesook T., Lane, William J., Li, Shuqiang, Livak, Kenneth J., Ho, Vincent T., Ritz, Jerome, Soiffer, Robert J., Keskin, Derin B., Stewart, Chip, Gusev, Alexander, Getz, Gad, and Wu, Catherine J.

Published
2023
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33. Key Parameters of Tumor Epitope Immunogenicity Revealed Through a Consortium Approach Improve Neoantigen Prediction

Author

Wells, Daniel K., primary, van Buuren, Marit M., additional, Dang, Kristen K., additional, Hubbard-Lucey, Vanessa M., additional, Sheehan, Kathleen C.F., additional, Campbell, Katie M., additional, Lamb, Andrew, additional, Ward, Jeffrey P., additional, Sidney, John, additional, Blazquez, Ana B., additional, Rech, Andrew J., additional, Zaretsky, Jesse M., additional, Comin-Anduix, Begonya, additional, Ng, Alphonsus H.C., additional, Chour, William, additional, Yu, Thomas V., additional, Rizvi, Hira, additional, Chen, Jia M., additional, Manning, Patrice, additional, Steiner, Gabriela M., additional, Doan, Xengie C., additional, Merghoub, Taha, additional, Guinney, Justin, additional, Kolom, Adam, additional, Selinsky, Cheryl, additional, Ribas, Antoni, additional, Hellmann, Matthew D., additional, Hacohen, Nir, additional, Sette, Alessandro, additional, Heath, James R., additional, Bhardwaj, Nina, additional, Ramsdell, Fred, additional, Schreiber, Robert D., additional, Schumacher, Ton N., additional, Kvistborg, Pia, additional, Defranoux, Nadine A., additional, Khan, Aly A., additional, Lugade, Amit, additional, Lazic, Ana M. Mijalkovic, additional, Frentzen, Angela A. Elizabeth, additional, Tadmor, Arbel D., additional, Sasson, Ariella S., additional, Rao, Arjun A., additional, Pei, Baikang, additional, Schrörs, Barbara, additional, Berent-Maoz, Beata, additional, Carreno, Beatriz M., additional, Song, Bin, additional, Peters, Bjoern, additional, Li, Bo, additional, Higgs, Brandon W., additional, Stevenson, Brian J., additional, Iseli, Christian, additional, Miller, Christopher A., additional, Morehouse, Christopher A., additional, Melief, Cornelis J.M., additional, Puig-Saus, Cristina, additional, van Beek, Daphne, additional, Balli, David, additional, Gfeller, David, additional, Haussler, David, additional, Jäger, Dirk, additional, Cortes, Eduardo, additional, Esaulova, Ekaterina, additional, Sherafat, Elham, additional, Arcila, Francisco, additional, Bartha, Gabor, additional, Liu, Geng, additional, Coukos, George, additional, Richard, Guilhem, additional, Chang, Han, additional, Si, Han, additional, Zörnig, Inka, additional, Xenarios, Ioannis, additional, Mandoiu, Ion, additional, Kooi, Irsan, additional, Conway, James P., additional, Kessler, Jan H., additional, Greenbaum, Jason A., additional, Perera, Jason F., additional, Harris, Jason, additional, Hundal, Jasreet, additional, Shelton, Jennifer M., additional, Wang, Jianmin, additional, Wang, Jiaqian, additional, Greshock, Joel, additional, Blake, Jonathon, additional, Szustakowski, Joseph, additional, Kodysh, Julia, additional, Forman, Juliet, additional, Wei, Lei, additional, Lee, Leo J., additional, Fanchi, Lorenzo F., additional, Slagter, Maarten, additional, Lang, Maren, additional, Mueller, Markus, additional, Lower, Martin, additional, Vormehr, Mathias, additional, Artyomov, Maxim N., additional, Kuziora, Michael, additional, Princiotta, Michael, additional, Bassani-Sternberg, Michal, additional, Macabali, Mignonette, additional, Kojicic, Milica R., additional, Yang, Naibo, additional, Raicevic, Nevena M. Ilic, additional, Guex, Nicolas, additional, Robine, Nicolas, additional, Halama, Niels, additional, Skundric, Nikola M., additional, Milicevic, Ognjen S., additional, Gellert, Pascal, additional, Jongeneel, Patrick, additional, Charoentong, Pornpimol, additional, Srivastava, Pramod K., additional, Tanden, Prateek, additional, Shah, Priyanka, additional, Hu, Qiang, additional, Gupta, Ravi, additional, Chen, Richard, additional, Petit, Robert, additional, Ziman, Robert, additional, Hilker, Rolf, additional, Shukla, Sachet A., additional, Al Seesi, Sahar, additional, Boyle, Sean M., additional, Qiu, Si, additional, Sarkizova, Siranush, additional, Salama, Sofie, additional, Liu, Song, additional, Wu, Song, additional, Sridhar, Sriram, additional, Ketelaars, Steven L.C., additional, Jhunjhunwala, Suchit, additional, Shcheglova, Tatiana, additional, Schuepbach, Thierry, additional, Creasy, Todd H., additional, Josipovic, Veliborka, additional, Kovacevic, Vladimir B., additional, Fu, Weixuan, additional, Krebber, Willem-Jan, additional, Hsu, Yi-Hsiang, additional, Sebastian, Yinong, additional, Yalcin, Zeynep Kosaloglu-, additional, and Huang, Zhiqin, additional

Published
2020
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34. A large peptidome dataset improves HLA class I epitope prediction across most of the human population

Author

Sarkizova, Siranush, primary, Klaeger, Susan, additional, Le, Phuong M., additional, Li, Letitia W., additional, Oliveira, Giacomo, additional, Keshishian, Hasmik, additional, Hartigan, Christina R., additional, Zhang, Wandi, additional, Braun, David A., additional, Ligon, Keith L., additional, Bachireddy, Pavan, additional, Zervantonakis, Ioannis K., additional, Rosenbluth, Jennifer M., additional, Ouspenskaia, Tamara, additional, Law, Travis, additional, Justesen, Sune, additional, Stevens, Jonathan, additional, Lane, William J., additional, Eisenhaure, Thomas, additional, Lan Zhang, Guang, additional, Clauser, Karl R., additional, Hacohen, Nir, additional, Carr, Steven A., additional, Wu, Catherine J., additional, and Keskin, Derin B., additional

Published
2019
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35. Abstract 566: Neoantigens from translated unannotated open reading frames in cancer

Author

Ouspenskaia, Tamara, primary, Law, Travis E., additional, Clauser, Karl R., additional, Klaeger, Susan, additional, Keskin, Derin B., additional, Li, Bo, additional, Christian, Elena, additional, Chow, Yuen Ting, additional, Le, Phuong M., additional, Gould, Joshua, additional, Ji, Zhe, additional, Zhang, Wandi, additional, Bachireddy, Pavan, additional, Sarkizova, Siranush, additional, Hacohen, Nir, additional, Carr, Steven A., additional, Wu, Catherine J., additional, and Regev, Aviv, additional

Published
2019
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36. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors

Author

Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Regev, Aviv, Villani, Alexandra-Chloé, Satija, Rahul, Reynolds, Gary, Sarkizova, Siranush, Shekhar, Karthik, Fletcher, James, Griesbeck, Morgane, Butler, Andrew, Zheng, Shiwei, Lazo, Suzan, Jardine, Laura, Dixon, David, Stephenson, Emily, Nilsson, Emil, Grundberg, Ida, McDonald, David, Filby, Andrew, Li, Weibo, De Jager, Philip L., Rozenblatt-Rosen, Orit, Lane, Andrew A., Haniffa, Muzlifah, Hacohen, Nir, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Regev, Aviv, Villani, Alexandra-Chloé, Satija, Rahul, Reynolds, Gary, Sarkizova, Siranush, Shekhar, Karthik, Fletcher, James, Griesbeck, Morgane, Butler, Andrew, Zheng, Shiwei, Lazo, Suzan, Jardine, Laura, Dixon, David, Stephenson, Emily, Nilsson, Emil, Grundberg, Ida, McDonald, David, Filby, Andrew, Li, Weibo, De Jager, Philip L., Rozenblatt-Rosen, Orit, Lane, Andrew A., Haniffa, Muzlifah, and Hacohen, Nir

Abstract

Dendritic cells (DCs) and monocytes play a central role in pathogen sensing, phagocytosis, and antigen presentation and consist of multiple specialized subtypes. However, their identities and interrelationships are not fully understood. Using unbiased single-cell RNA sequencing (RNA-seq) of ~2400 cells, we identified six human DCs and four monocyte subtypes in human blood. Our study reveals a new DC subset that shares properties with plasmacytoid DCs (pDCs) but potently activates T cells, thus redefining pDCs; a new subdivision within the CD1C+ subset of DCs; the relationship between blastic plasmacytoid DC neoplasia cells and healthy DCs; and circulating progenitor of conventional DCs (cDCs). Our revised taxonomy will enable more accurate functional and developmental analyses as well as immune monitoring in health and disease.

Published
2018

37. Aryl Hydrocarbon Receptor Controls Monocyte Differentiation into Dendritic Cells versus Macrophages

Author

Goudot, Christel, primary, Coillard, Alice, additional, Villani, Alexandra-Chloé, additional, Gueguen, Paul, additional, Cros, Adeline, additional, Sarkizova, Siranush, additional, Tang-Huau, Tsing-Lee, additional, Bohec, Mylène, additional, Baulande, Sylvain, additional, Hacohen, Nir, additional, Amigorena, Sebastian, additional, and Segura, Elodie, additional

Published
2017
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38. Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Harbors Frequent Splicesosome Mutations That Cause Aberrant RNA Splicing Affecting Genes Critical in pDC Differentiation and Function

Author

Togami, Katsuhiro, primary, Madan, Vikas, additional, Li, Jia, additional, Villani, Alexandra-Chloe, additional, Sarkizova, Siranush, additional, Ghandi, Mahmoud, additional, Buczkowski, Kevin, additional, Li, Yvonne, additional, Biichle, Sabeha, additional, Angelot-Delettre, Fanny, additional, Seiler, Michael, additional, Buonamici, Silvia, additional, Taylor, Justin, additional, Abdel-Wahab, Omar, additional, Hammerman, Peter S, additional, Hacohen, Nir, additional, Yang, Henry, additional, Garnache-Ottou, Francine, additional, Koeffler, H. Phillip, additional, and Lane, Andrew A., additional

Published
2016
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40. Systematic Prediction of Minor Histocompatibility Antigens to Inform GvHD Outcomes after Allogeneic Stem Cell Transplantation

Author

Cieri, Nicoletta, Hookeri, Nidhi, Stromhaug, Kari, Li, Liang, Keating, Julia, Stevens, Jonathan, Kooshesh, Kameron, Ji, Helen, Hernandez, Gabrielle M., Abelin, Jennifer, Klaeger, Susan, Forman, Cleo, Clauser, Karl, Sarkizova, Siranush, Oliveira, Giacomo, Penter, Livius, Kim, Haesook T., Lane, William, Li, Shuqiang, Livak, Kenneth J., Carr, Steven A., Keskin, Derin B., Ho, Vincent T., Ritz, Jerome, Soiffer, Robert J., Neuberg, Donna S., Stewart, Chip, Getz, Gad, and Wu, Catherine J

Abstract

T cell alloreactivity against minor histocompatibility antigens (mHAgs), polymorphic peptides resulting from donor-recipient (D-R) disparity at sites of genetic polymorphisms (SNPs, indels, frameshifts), is at the core of the therapeutic effect of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Despite the crucial role of mHAgs in graft-versus-leukemia and graft-versus-host (GvHD) reactions, it has not been possible thus far to consistently link patient-specific mHAg repertoires to clinical outcomes. As a result, only D-R HLA matching and the activity of GvHD prophylaxis strategies are currently available to help clinicians in this challenge.

Published
2023
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41. Two distinct colonic CD14+subsets characterized by single-cell RNA profiling in Crohn’s disease

Author

Chapuy, Laurence, Bsat, Marwa, Sarkizova, Siranush, Rubio, Manuel, Therrien, Amélie, Wassef, Evelyne, Bouin, Mickael, Orlicka, Katarzina, Weber, Audrey, Hacohen, Nir, Villani, Alexandra-Chloé, and Sarfati, Marika

Abstract

Inflammatory bowel diseases are associated with dysregulated immune responses in the intestinal tissue. Four molecularly identified macrophage subsets control immune homeostasis in healthy gut. However, the specific roles and transcriptomic profiles of the phenotypically heterogeneous CD14+macrophage-like population in inflamed gut remain to be investigated in Crohn’s disease (CD). Here we identified two phenotypically, morphologically and functionally distinct colonic HLADR+SIRPα+CD14+subpopulations that were further characterized using single-cell RNA-sequencing (scRNAseq) in CD. Frequencies of CD64hiCD163−/dimcells selectively augmented in inflamed colon and correlated with endoscopic score of disease severity. IL-1β and IL-23-producing CD64hiCD163−/dimcells predominated over TNF-α-producing CD64hiCD163hicells in lesions. Purified “inflammatory monocyte-like” CD163−, but not “macrophage-like” CD163hicells, through IL-1β, promoted Th17/Th1 but not Th1 responses in tissue memory CD4+T cells. Unsupervised scRNAseq analysis that captures the entire HLADR+SIRPα+population revealed six clusters, two of which were enriched in either CD163−or CD163hicells, and best defined by TREM1/FCAR/FCN1/IL1RNor CD209/MERTK/MRCI/CD163L1genes, respectively. Selected newly identified discriminating markers were used beyond CD163 to isolate cells that shared pro-Th17/Th1 function with CD163−cells. In conclusion, a molecularly distinct pro-inflammatory CD14+subpopulation accumulates in inflamed colon, drives intestinal inflammatory T-cell responses, and thus, might contribute to CD disease severity.

Published
2019
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42. Mass spectrometry-based HLA-II peptidomics combined with multi-omics will aid the development of future immunotherapies

Author

Taylor, Hannah B., Klaeger, Susan, Clauser, Karl R., Sarkizova, Siranush, Weingarten-Gabbay, Shira, Graham, Daniel B., Carr, Steven A., and Abelin, Jennifer G.

Abstract

Immunotherapies have emerged to treat diseases by selectively modulating a patient’s immune response. Although the roles of T and B cells in adaptive immunity have been well studied, it remains difficult to select targets for immunotherapeutic strategies. Because human leukocyte antigen class II (HLA-II) peptides activate CD4+ T cells and regulate B cell activation, proliferation, and differentiation, these peptide antigens represent a class of potential immunotherapy targets and biomarkers. To better understand the molecular basis of how HLA-II antigen presentation is involved in disease progression and treatment, systematic HLA-II peptidomics combined with multi-omic analyses of diverse cell types in healthy and diseased states is required. For this reason, mass spectrometry based innovations that facilitate investigations into the interplay between disease pathologies and the presentation of HLA-II peptides to CD4+ T cells will aid in the development of patient focused immunotherapies.

Published
2021
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44. Systematic identification of minor histocompatibility antigens predicts outcomes of allogeneic hematopoietic cell transplantation.

Author

Cieri N, Hookeri N, Stromhaug K, Li L, Keating J, Díaz-Fernández P, Gómez-García de Soria V, Stevens J, Kfuri-Rubens R, Shao Y, Kooshesh KA, Powell K, Ji H, Hernandez GM, Abelin J, Klaeger S, Forman C, Clauser KR, Sarkizova S, Braun DA, Penter L, Kim HT, Lane WJ, Oliveira G, Kean LS, Li S, Livak KJ, Carr SA, Keskin DB, Muñoz-Calleja C, Ho VT, Ritz J, Soiffer RJ, Neuberg D, Stewart C, Getz G, and Wu CJ

Abstract

T cell alloreactivity against minor histocompatibility antigens (mHAgs)-polymorphic peptides resulting from donor-recipient (D-R) disparity at sites of genetic polymorphisms-is at the core of the therapeutic effect of allogeneic hematopoietic cell transplantation (allo-HCT). Despite the crucial role of mHAgs in graft-versus-leukemia (GvL) and graft-versus-host disease (GvHD) reactions, it remains challenging to consistently link patient-specific mHAg repertoires to clinical outcomes. Here we devise an analytic framework to systematically identify mHAgs, including their detection on HLA class I ligandomes and functional verification of their immunogenicity. The method relies on the integration of polymorphism detection by whole-exome sequencing of germline DNA from D-R pairs with organ-specific transcriptional- and proteome-level expression. Application of this pipeline to 220 HLA-matched allo-HCT D-R pairs demonstrated that total and organ-specific mHAg load could independently predict the occurrence of acute GvHD and chronic pulmonary GvHD, respectively, and defined promising GvL targets, confirmed in a validation cohort of 58 D-R pairs, for the prevention or treatment of post-transplant disease recurrence., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Published
2024
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45. Unsupervised Protein-Ligand Binding Energy Prediction via Neural Euler's Rotation Equation.

Author

Jin W, Sarkizova S, Chen X, Hacohen N, and Uhler C

Abstract

Protein-ligand binding prediction is a fundamental problem in AI-driven drug discovery. Prior work focused on supervised learning methods using a large set of binding affinity data for small molecules, but it is hard to apply the same strategy to other drug classes like antibodies as labelled data is limited. In this paper, we explore unsupervised approaches and reformulate binding energy prediction as a generative modeling task. Specifically, we train an energy-based model on a set of unlabelled protein-ligand complexes using SE(3) denoising score matching and interpret its log-likelihood as binding affinity. Our key contribution is a new equivariant rotation prediction network called Neural Euler's Rotation Equations (NERE) for SE(3) score matching. It predicts a rotation by modeling the force and torque between protein and ligand atoms, where the force is defined as the gradient of an energy function with respect to atom coordinates. We evaluate NERE on protein-ligand and antibody-antigen binding affinity prediction benchmarks. Our model outperforms all unsupervised baselines (physics-based and statistical potentials) and matches supervised learning methods in the antibody case.

Published
2023

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