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1. The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity

Author

Baumgartner, Christina K., Ebrahimi-Nik, Hakimeh, Iracheta-Vellve, Arvin, Hamel, Keith M., Olander, Kira E., Davis, Thomas G. R., McGuire, Kathleen A., Halvorsen, Geoff T., Avila, Omar I., Patel, Chirag H., Kim, Sarah Y., Kammula, Ashwin V., Muscato, Audrey J., Halliwill, Kyle, Geda, Prasanthi, Klinge, Kelly L., Xiong, Zhaoming, Duggan, Ryan, Mu, Liang, Yeary, Mitchell D., Patti, James C., Balon, Tyler M., Mathew, Rebecca, Backus, Carey, Kennedy, Domenick E., Chen, Angeline, Longenecker, Kenton, Klahn, Joseph T., Hrusch, Cara L., Krishnan, Navasona, Hutchins, Charles W., Dunning, Jax P., Bulic, Marinka, Tiwari, Payal, Colvin, Kayla J., Chuong, Cun Lan, Kohnle, Ian C., Rees, Matthew G., Boghossian, Andrew, Ronan, Melissa, Roth, Jennifer A., Wu, Meng-Ju, Suermondt, Juliette S. M. T., Knudsen, Nelson H., Cheruiyot, Collins K., Sen, Debattama R., Griffin, Gabriel K., Golub, Todd R., El-Bardeesy, Nabeel, Decker, Joshua H., Yang, Yi, Guffroy, Magali, Fossey, Stacey, Trusk, Patricia, Sun, Im-Meng, Liu, Yue, Qiu, Wei, Sun, Qi, Paddock, Marcia N., Farney, Elliot P., Matulenko, Mark A., Beauregard, Clay, Frost, Jennifer M., Yates, Kathleen B., Kym, Philip R., and Manguso, Robert T.

Published
2023
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2. Leukemia-intrinsic determinants of CAR-T response revealed by iterative in vivo genome-wide CRISPR screening

Author

Ramos, Azucena, Koch, Catherine E., Liu-Lupo, Yunpeng, Hellinger, Riley D., Kyung, Taeyoon, Abbott, Keene L., Fröse, Julia, Goulet, Daniel, Gordon, Khloe S., Eidell, Keith P., Leclerc, Paul, Whittaker, Charles A., Larson, Rebecca C., Muscato, Audrey J., Yates, Kathleen B., Dubrot, Juan, Doench, John G., Regev, Aviv, Vander Heiden, Matthew G., Maus, Marcela V., Manguso, Robert T., Birnbaum, Michael E., and Hemann, Michael T.

Published
2023
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3. Targeting TBK1 to overcome resistance to cancer immunotherapy

Author

Sun, Yi, Revach, Or-yam, Anderson, Seth, Kessler, Emily A., Wolfe, Clara H., Jenney, Anne, Mills, Caitlin E., Robitschek, Emily J., Davis, Thomas G. R., Kim, Sarah, Fu, Amina, Ma, Xiang, Gwee, Jia, Tiwari, Payal, Du, Peter P., Sindurakar, Princy, Tian, Jun, Mehta, Arnav, Schneider, Alexis M., Yizhak, Keren, Sade-Feldman, Moshe, LaSalle, Thomas, Sharova, Tatyana, Xie, Hongyan, Liu, Shuming, Michaud, William A., Saad-Beretta, Rodrigo, Yates, Kathleen B., Iracheta-Vellve, Arvin, Spetz, Johan K. E., Qin, Xingping, Sarosiek, Kristopher A., Zhang, Gao, Kim, Jong Wook, Su, Mack Y., Cicerchia, Angelina M., Rasmussen, Martin Q., Klempner, Samuel J., Juric, Dejan, Pai, Sara I., Miller, David M., Giobbie-Hurder, Anita, Chen, Jonathan H., Pelka, Karin, Frederick, Dennie T., Stinson, Susanna, Ivanova, Elena, Aref, Amir R., Paweletz, Cloud P., Barbie, David A., Sen, Debattama R., Fisher, David E., Corcoran, Ryan B., Hacohen, Nir, Sorger, Peter K., Flaherty, Keith T., Boland, Genevieve M., Manguso, Robert T., and Jenkins, Russell W.

Published
2023
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4. In vivo CRISPR screens reveal the landscape of immune evasion pathways across cancer

Author

Dubrot, Juan, Du, Peter P., Lane-Reticker, Sarah Kate, Kessler, Emily A., Muscato, Audrey J., Mehta, Arnav, Freeman, Samuel S., Allen, Peter M., Olander, Kira E., Ockerman, Kyle M., Wolfe, Clara H., Wiesmann, Fabius, Knudsen, Nelson H., Tsao, Hsiao-Wei, Iracheta-Vellve, Arvin, Schneider, Emily M., Rivera-Rosario, Andrea N., Kohnle, Ian C., Pope, Hans W., Ayer, Austin, Mishra, Gargi, Zimmer, Margaret D., Kim, Sarah Y., Mahapatra, Animesh, Ebrahimi-Nik, Hakimeh, Frederick, Dennie T., Boland, Genevieve M., Haining, W. Nicholas, Root, David E., Doench, John G., Hacohen, Nir, Yates, Kathleen B., and Manguso, Robert T.

Published
2022
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5. Innate immune activation restricts priming and protective efficacy of the radiation-attenuated PfSPZ malaria vaccine

Author

Senkpeil, Leetah, primary, Bhardwaj, Jyoti, additional, Little, Morgan R., additional, Holla, Prasida, additional, Upadhye, Aditi, additional, Fusco, Elizabeth M., additional, Swanson II, Phillip A., additional, Wiegand, Ryan E., additional, Macklin, Michael D., additional, Bi, Kevin, additional, Flynn, Barbara J., additional, Yamamoto, Ayako, additional, Gaskin, Erik L., additional, Sather, D. Noah, additional, Oblak, Adrian L., additional, Simpson, Edward, additional, Gao, Hongyu, additional, Haining, W. Nicholas, additional, Yates, Kathleen B., additional, Liu, Xiaowen, additional, Murshedkar, Tooba, additional, Richie, Thomas L., additional, Sim, B. Kim Lee, additional, Otieno, Kephas, additional, Kariuki, Simon, additional, Xuei, Xiaoling, additional, Liu, Yunlong, additional, Polidoro, Rafael B., additional, Hoffman, Stephen L., additional, Oneko, Martina, additional, Steinhardt, Laura C., additional, Schmidt, Nathan W., additional, Seder, Robert A., additional, and Tran, Tuan M., additional

Published
2024
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6. Maintenance of CD4 T cell fitness through regulation of Foxo1

Author

Newton, Ryan H, Shrestha, Sharad, Sullivan, Jenna M, Yates, Kathleen B, Compeer, Ewoud B, Ron-Harel, Noga, Blazar, Bruce R, Bensinger, Steven J, Haining, W Nicholas, Dustin, Michael L, Campbell, Daniel J, Chi, Hongbo, and Turka, Laurence A

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Biodefense, Genetics, Prevention, Vaccine Related, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Animals, CD4-Positive T-Lymphocytes, Cell Proliferation, Cells, Cultured, Cholesterol, Forkhead Box Protein O1, Gene Expression Profiling, Homeostasis, Immunological Synapses, Interleukin-2 Receptor beta Subunit, Lymphocyte Activation, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Knockout, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-myc, Signal Transduction, T-Lymphocytes, Regulatory, Immunology, Biochemistry and cell biology
Abstract

Foxo transcription factors play an essential role in regulating specialized lymphocyte functions and in maintaining T cell quiescence. Here, we used a system in which Foxo1 transcription-factor activity, which is normally terminated upon cell activation, cannot be silenced, and we show that enforcing Foxo1 activity disrupts homeostasis of CD4 conventional and regulatory T cells. Despite limiting cell metabolism, continued Foxo1 activity is associated with increased activation of the kinase Akt and a cell-intrinsic proliferative advantage; however, survival and cell division are decreased in a competitive setting or growth-factor-limiting conditions. Via control of expression of the transcription factor Myc and the IL-2 receptor β-chain, termination of Foxo1 signaling couples the increase in cellular cholesterol to biomass accumulation after activation, thereby facilitating immunological synapse formation and mTORC1 activity. These data reveal that Foxo1 regulates the integration of metabolic and mitogenic signals essential for T cell competitive fitness and the coordination of cell growth with cell division.

Published
2018

8. Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity

Author

Griffin, Gabriel K., Wu, Jingyi, Iracheta-Vellve, Arvin, Patti, James C., Hsu, Jeffrey, Davis, Thomas, Dele-Oni, Deborah, Du, Peter P., Halawi, Aya G., Ishizuka, Jeffrey J., Kim, Sarah Y., Klaeger, Susan, Knudsen, Nelson H., Miller, Brian C., Nguyen, Tung H., Olander, Kira E., Papanastasiou, Malvina, Rachimi, Suzanna, Robitschek, Emily J., Schneider, Emily M., Yeary, Mitchell D., Zimmer, Margaret D., Jaffe, Jacob D., Carr, Steven A., Doench, John G., Haining, W. Nicholas, Yates, Kathleen B., Manguso, Robert T., and Bernstein, Bradley E.

Published
2021
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9. The epigenetic landscape of T cell exhaustion

Author

Sen, Debattama R, Kaminski, James, Barnitz, R Anthony, Kurachi, Makoto, Gerdemann, Ulrike, Yates, Kathleen B, Tsao, Hsiao-Wei, Godec, Jernej, LaFleur, Martin W, Brown, Flavian D, Tonnerre, Pierre, Chung, Raymond T, Tully, Damien C, Allen, Todd M, Frahm, Nicole, Lauer, Georg M, Wherry, E John, Yosef, Nir, and Haining, W Nicholas

Subjects
Genetics, Infectious Diseases, Prevention, Human Genome, 1.1 Normal biological development and functioning, Underpinning research, Infection, Animals, B7-H1 Antigen, CD8-Positive T-Lymphocytes, Cell Lineage, Chromatin, Chronic Disease, Disease Models, Animal, Enhancer Elements, Genetic, Epigenesis, Genetic, Gene Editing, HIV Infections, Hepatitis C, Chronic, Humans, Immunologic Memory, Immunotherapy, Lymphocytic Choriomeningitis, Mice, Mice, Inbred C57BL, SOXB1 Transcription Factors, T-Box Domain Proteins, Transcription, Genetic, General Science & Technology
Abstract

Exhausted T cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (PD-1). However, the regulation of gene expression in exhausted T cells is poorly understood. Here, we define the accessible chromatin landscape in exhausted CD8+ T cells and show that it is distinct from functional memory CD8+ T cells. Exhausted CD8+ T cells in humans and a mouse model of chronic viral infection acquire a state-specific epigenetic landscape organized into functional modules of enhancers. Genome editing shows that PD-1 expression is regulated in part by an exhaustion-specific enhancer that contains essential RAR, T-bet, and Sox3 motifs. Functional enhancer maps may offer targets for genome editing that alter gene expression preferentially in exhausted CD8+ T cells.

Published
2016

10. Antigen presentation deficiency, mesenchymal differentiation, and resistance to immunotherapy in the murine syngeneic CT2A tumor model

Author

Iorgulescu, J. Bryan, primary, Ruthen, Neil, additional, Ahn, Ryuhjin, additional, Panagioti, Eleni, additional, Gokhale, Prafulla C., additional, Neagu, Martha, additional, Speranza, Maria C., additional, Eschle, Benjamin K., additional, Soroko, Kara M., additional, Piranlioglu, Raziye, additional, Datta, Meenal, additional, Krishnan, Shanmugarajan, additional, Yates, Kathleen B., additional, Baker, Gregory J., additional, Jain, Rakesh K., additional, Suvà, Mario L., additional, Neuberg, Donna, additional, White, Forest M., additional, Chiocca, E. Antonio, additional, Freeman, Gordon J., additional, Sharpe, Arlene H., additional, Wu, Catherine J., additional, and Reardon, David A., additional

Published
2023
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11. 999 The PTPN2/N1 small molecule inhibitor ABBV-CLS-484 promotes NK cell activity driving primary tumor regression and preventing metastasis

Author

Patel, Chirag, primary, McGuire, Kathleen A, additional, Ebrahimi-Nik, Hakimeh, additional, Sun, Meng, additional, Liu, Yue, additional, Klinge, Kelly, additional, Aguado, Jacqueline, additional, Muscato, Audrey J, additional, Tiwari, Payal, additional, Avila-Monge, Omar, additional, Colvin, Kayla J, additional, Olander, Kira, additional, Halliwill, Kyle, additional, Klahn, Joseph, additional, Schutte, Alexander, additional, Paddock, Marcia N, additional, Powell, Jonathan, additional, Hamel, Keith M, additional, Frost, Jennifer M, additional, Yates, Kathleen B, additional, Kym, Philip R, additional, Manguso, Robert T, additional, and Baumgartner, Christina K, additional

Published
2023
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12. 1403-A PTPN2/N1 inhibitor ABBV-CLS-484 unleashes potent anti-tumor immunity

Author

Ebrahimi-Nik, Hakimeh, primary, Baumgartner, Christina K, additional, Iracheta-Vellve, Arvin, additional, Hamel, Keith M, additional, Olander, Kira, additional, Davis, Thomas GR, additional, McGuire, Kathleen A, additional, Halvorsen, Geoff T, additional, Avila, Omar I, additional, Patel, Chirag, additional, Kim, Sarah, additional, Kammula, Ashwin V, additional, Muscato, Audrey J, additional, Halliwill, Kyle, additional, Geda, Prasanthi, additional, Klinge, Kelly, additional, Xiong, Zhaoming, additional, Duggan, Ryan, additional, Mu, Liang, additional, Yeary, Mitchell D, additional, Patti, James C, additional, Balon, Tyler M, additional, Mathew, Rebecca, additional, Backus, Carey, additional, Kennedy, Domenick, additional, Chen, Angeline, additional, Longenecker, Kenton, additional, Klahn, Joseph, additional, Hrusch, Cara, additional, Krishnan, Navasona, additional, Hutchins, Charles W, additional, Aguado, Jacqueline, additional, Bulic, Marinka, additional, Tiwari, Payal, additional, Colvin, Kayla J, additional, Chuong, Cun Lan, additional, Kohnle, Ian C, additional, Rees, Matthew G, additional, Boghossian, Andrew, additional, Ronan, Melissa, additional, Roth, Jennifer A, additional, Wu, Meng-Ju, additional, Sen, Debattama R, additional, Griffin, Gabriel K, additional, El-Bardeesy, Nabeel, additional, Trusk, Patricia, additional, Sun, Meng, additional, Liu, Yue, additional, Decker, Joshua H, additional, Yang, Yi, additional, Fossey, Stacey, additional, Qiu, Wei, additional, Sun, Qi, additional, Paddock, Marcia N, additional, Farney, Elliot P, additional, Beauregard, Clay, additional, Frost, Jennifer M, additional, Yates, Kathleen B, additional, Kym, Philip R, additional, and Manguso, Robert T, additional

Published
2023
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13. Fibroblastic reticular cells enhance T cell metabolism and survival via epigenetic remodeling

Author

Brown, Flavian D., Sen, Debattama R., LaFleur, Martin W., Godec, Jernej, Lukacs-Kornek, Veronika, Schildberg, Frank A., Kim, Hye-Jung, Yates, Kathleen B., Ricoult, Stéphane J. H., Bi, Kevin, Trombley, Justin D., Kapoor, Varun N., Stanley, Illana A., Cremasco, Viviana, Danial, Nika N., Manning, Brendan D., Sharpe, Arlene H., Haining, W. Nicholas, and Turley, Shannon J.

Published
2019
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15. Antigen presentation deficiency, mesenchymal differentiation, and resistance to immunotherapy in the murine syngeneic CT2A tumor model.

Author

Iorgulescu, J. Bryan, Ruthen, Neil, Ryuhjin Ahn, Panagioti, Eleni, Gokhale, Prafulla C., Neagu, Martha, Speranza, Maria C., Eschle, Benjamin K., Soroko, Kara M., Piranlioglu, Raziye, Datta, Meenal, Krishnan, Shanmugarajan, Yates, Kathleen B., Baker, Gregory J., Jain, Rakesh K., Suvà, Mario L., Neuberg, Donna, White, Forest M., Chiocca, E. Antonio, and Freeman, Gordon J.

Subjects
ANTIGEN presentation, HUMAN biology, RAS oncogenes, IMMUNOTHERAPY, PROTEIN analysis
Abstract

Background: The GL261 and CT2A syngeneic tumor lines are frequently used as immunocompetent orthotopic mouse models of human glioblastoma (huGBM) but demonstrate distinct differences in their responses to immunotherapy. Methods: To decipher the cell-intrinsic mechanisms that drive immunotherapy resistance in CT2A-luc and to define the aspects of human cancer biology that these lines can best model, we systematically compared their characteristics using whole exome and transcriptome sequencing, and protein analysis through immunohistochemistry, Western blot, flow cytometry, immunopeptidomics, and phosphopeptidomics. Results: The transcriptional profiles of GL261-luc2 and CT2A-luc tumors resembled those of some huGBMs, despite neither line sharing the essential genetic or histologic features of huGBM. Both models exhibited striking hypermutation, with clonal hotspot mutations in RAS genes (Kras p.G12C in GL261-luc2 and Nras p.Q61L in CT2A-luc). CT2A-luc distinctly displayed mesenchymal differentiation, upregulated angiogenesis, and multiple defects in antigen presentation machinery (e.g. Tap1 p.Y488C and Psmb8 p.A275P mutations) and interferon response pathways (e.g. copy number losses of loci including IFN genes and reduced phosphorylation of JAK/STAT pathway members). The defect in MHC class I expression could be overcome in CT2Aluc by interferon-g treatment, which may underlie the modest efficacy of some immunotherapy combinations. Additionally, CT2A-luc demonstrated substantial baseline secretion of the CCL-2, CCL-5, and CCL-22 chemokines, which play important roles as myeloid chemoattractants. Conclusion: Although the clinical contexts that can be modeled by GL261 and CT2A for huGBM are limited, CT2A may be an informative model of immunotherapy resistance due to its deficits in antigen presentation machinery and interferon response pathways. [ABSTRACT FROM AUTHOR]

Published
2024
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16. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade

Author

Miller, Brian C., Sen, Debattama R., Al Abosy, Rose, Bi, Kevin, Virkud, Yamini V., LaFleur, Martin W., Yates, Kathleen B., Lako, Ana, Felt, Kristen, Naik, Girish S., Manos, Michael, Gjini, Evisa, Kuchroo, Juhi R., Ishizuka, Jeffrey J., Collier, Jenna L., Griffin, Gabriel K., Maleri, Seth, Comstock, Dawn E., Weiss, Sarah A., Brown, Flavian D., Panda, Arpit, Zimmer, Margaret D., Manguso, Robert T., Hodi, F. Stephen, Rodig, Scott J., Sharpe, Arlene H., and Haining, W. Nicholas

Published
2019
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17. Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade

Author

Ishizuka, Jeffrey J., Manguso, Robert T., Cheruiyot, Collins K., Bi, Kevin, Panda, Arpit, Iracheta-Vellve, Arvin, Miller, Brian C., Du, Peter P., Yates, Kathleen B., Dubrot, Juan, Buchumenski, Ilana, Comstock, Dawn E., Brown, Flavian D., Ayer, Austin, Kohnle, Ian C., Pope, Hans W., Zimmer, Margaret D., Sen, Debattama R., Lane-Reticker, Sarah K., Robitschek, Emily J., Griffin, Gabriel K., Collins, Natalie B., Long, Adrienne H., Doench, John G., Kozono, David, Levanon, Erez Y., and Haining, W. Nicholas

Published
2019
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20. Abstract A41: Small molecule inhibition of PTPN2/1 inflames the tumour microenvironment and unleashes potent CD8+ T cell immunity

Author

Ebrahimi-Nik, Hakimeh, primary, Iracheta-Vellve, Arvin, additional, Olander, Kira E., additional, Davis, Thomas R.G., additional, Kim, Sarah Y., additional, Yeary, Mitchell D., additional, Patti, James C., additional, Balon, Tyler M., additional, Avila, Omar Ismail, additional, Chuong, Cun Lan, additional, Wu, Meng-Ju, additional, Baumgartner, Christina K., additional, Hamel, Keith M., additional, McGuire, Kathleen A., additional, Mathew, Rebecca, additional, Backus, Carey, additional, Kohnle, Ian C., additional, Xiong, Zhaoming, additional, Farney, Elliot P., additional, Frost, Jennifer M., additional, Halvorsen, Geoff T., additional, Rees, Matthew, additional, Boghossian, Andrew, additional, Ronan, Melissa, additional, Roth, Jennifer A., additional, Golub, Todd R., additional, Griffin, Gabriel K., additional, El-Bardeesy, Nabeel, additional, Beauregard, Clay C., additional, Kym, Philip R., additional, Yates, Kathleen B., additional, and Manguso, Robert T., additional

Published
2022
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21. Vaccine-elicited CD4 T cells induce immunopathology after chronic LCMV infection

Author

Penaloza-MacMaster, Pablo, Barber, Daniel L., Wherry, E. John, Provine, Nicholas M., Teigler, Jeffrey E., Parenteau, Lily, Blackmore, Stephen, Borducchi, Erica N., Larocca, Rafael A., Yates, Kathleen B., Shen, Hao, Haining, W. Nicholas, Sommerstein, Rami, Pinschewer, Daniel D., Ahmed, Rafi, and Barouch, Dan H.

Published
2015

22. Author Correction: Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade

Author

Miller, Brian C., Sen, Debattama R., Al Abosy, Rose, Bi, Kevin, Virkud, Yamini V., LaFleur, Martin W., Yates, Kathleen B., Lako, Ana, Felt, Kristen, Naik, Girish S., Manos, Michael, Gjini, Evisa, Kuchroo, Juhi R., Ishizuka, Jeffrey J., Collier, Jenna L., Griffin, Gabriel K., Maleri, Seth, Comstock, Dawn E., Weiss, Sarah A., Brown, Flavian D., Panda, Arpit, Zimmer, Margaret D., Manguso, Robert T., Hodi, F. Stephen, Rodig, Scott J., Sharpe, Arlene H., and Haining, W. Nicholas

Published
2019
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23. Abstract 3610: In vivo CRISPR screens reveal the landscape of immune evasion pathways across cancer

Author

Dubrot, Juan, primary, Du, Peter P., additional, Lane-Reticker, Sarah Kate, additional, Kessler, Emily A., additional, Muscato, Audrey J., additional, Mehta, Arnav, additional, Freeman, Samuel S., additional, Allen, Peter M., additional, Olander, Kira E., additional, Ockerman, Kyle M., additional, Wolfe, Clara H., additional, Wiesmann, Fabius, additional, Knudsen, Nelson H., additional, Tsao, Hsiao-Wei, additional, Iracheta-Vellve, Arvin, additional, Schneider, Emily M., additional, Rivera-Rosario, Andrea N., additional, Kohnle, Ian C., additional, Pope, Hans W., additional, Ayer, Austin, additional, Mishra, Gargi, additional, Zimmer, Margaret D., additional, Kim, Sarah Y., additional, Mahapatra, Animesh, additional, Ebrahimi-Nik, Hakimeh, additional, Frederick, Dennie T., additional, Boland, Genevieve M., additional, Haining, W. Nicholas, additional, Root, David E., additional, Doench, John G., additional, Hacohen, Nir, additional, Yates, Kathleen B., additional, and Manguso, Robert T., additional

Published
2022
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24. Abstract 606: Targeting the immune checkpoint PTPN2 with ABBV-CLS-484 inflames the tumor microenvironment and unleashes potent CD8+ T cell immunity

Author

Iracheta-Vellve, Arvin, primary, Ebrahimi-Nik, Hakimeh, additional, Davis, Thomas R., additional, Olander, Kira E., additional, Kim, Sarah Y., additional, Yeary, Mitchell D., additional, Patti, James C., additional, Kohnle, Ian C., additional, Baumgartner, Christina K., additional, Hamel, Keith M., additional, McGuire, Kathleen A., additional, Chuong, Cun Lan, additional, Xiong, Zhaoming, additional, Farney, Elliot P., additional, Frost, Jennifer M., additional, Rees, Matthew, additional, Boghossian, Andrew, additional, Ronan, Melissa, additional, Roth, Jennifer A., additional, Golub, Todd R., additional, Griffin, Gabriel K., additional, Beauregard, Clay, additional, Kym, Philip R., additional, Yates, Kathleen B., additional, and Manguso, Robert T., additional

Published
2022
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25. Abstract ND06: ABBV-CLS-484: An active site PTPN2/N1 inhibitor that augments the immune response and sensitizes tumors to immune-mediated killing

Author

Baumgartner, Christina K., primary, Paddock, Marcia N., additional, Frost, Jennifer M., additional, Hamel, Keith M., additional, McGuire, Kathleen A., additional, Halliwill, Kyle, additional, Xiong, Zhaoming, additional, Mu, Liang, additional, Klinge, Kelly, additional, Geda, Prasanthi, additional, Aguado, Jaqueline, additional, Bulic, Marinka, additional, Farney, Elliot P., additional, Yates, Kathleen B., additional, Manguso, Robert T., additional, Beauregard, Clay, additional, and Kym, Philip R., additional

Published
2022
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26. PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment

Author

Collins, Natalie B, primary, Al Abosy, Rose, additional, Miller, Brian C, additional, Bi, Kevin, additional, Zhao, Qihong, additional, Quigley, Michael, additional, Ishizuka, Jeffrey J, additional, Yates, Kathleen B, additional, Pope, Hans W, additional, Manguso, Robert T, additional, Shrestha, Yashaswi, additional, Wadsworth, Marc, additional, Hughes, Travis, additional, Shalek, Alex K, additional, Boehm, Jesse S, additional, Hahn, William C, additional, Doench, John G, additional, and Haining, W Nicholas, additional

Published
2022
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27. Innate immune activation restricts priming and protective efficacy of the radiation-attenuated PfSPZ malaria vaccine

Author

Senkpeil, Leetah, primary, Bhardwaj, Jyoti, additional, Little, Morgan, additional, Holla, Prasida, additional, Upadhye, Aditi, additional, Swanson, Phillip A., additional, Wiegand, Ryan E., additional, Macklin, Michael D., additional, Bi, Kevin, additional, Flynn, Barbara J., additional, Yamamoto, Ayako, additional, Gaskin, Erik L., additional, Sather, D. Noah, additional, Oblak, Adrian L., additional, Simpson, Edward, additional, Gao, Hongyu, additional, Haining, W. Nicholas, additional, Yates, Kathleen B., additional, Liu, Xiaowen, additional, Otieno, Kephas, additional, Kariuki, Simon, additional, Xuei, Xiaoling, additional, Liu, Yunlong, additional, Polidoro, Rafael, additional, Hoffman, Stephen L., additional, Oneko, Martina, additional, Steinhardt, Laura C., additional, Schmidt, Nathan W., additional, Seder, Robert A., additional, and Tran, Tuan M., additional

Published
2021
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28. TISMO: syngeneic mouse tumor database to model tumor immunity and immunotherapy response

Author

Zeng, Zexian, primary, Wong, Cheryl J, additional, Yang, Lin, additional, Ouardaoui, Nofal, additional, Li, Dian, additional, Zhang, Wubing, additional, Gu, Shengqing, additional, Zhang, Yi, additional, Liu, Yang, additional, Wang, Xiaoqing, additional, Fu, Jingxin, additional, Zhou, Liye, additional, Zhang, Boning, additional, Kim, Sarah, additional, Yates, Kathleen B, additional, Brown, Myles, additional, Freeman, Gordon J, additional, Uppaluri, Ravindra, additional, Manguso, Robert, additional, and Liu, X Shirley, additional

Published
2021
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31. In vivo screens using a selective CRISPR antigen removal lentiviral vector system reveal immune dependencies in renal cell carcinoma

Author

Dubrot, Juan, primary, Lane-Reticker, Sarah Kate, additional, Kessler, Emily A., additional, Ayer, Austin, additional, Mishra, Gargi, additional, Wolfe, Clara H., additional, Zimmer, Margaret D., additional, Du, Peter P., additional, Mahapatra, Animesh, additional, Ockerman, Kyle M., additional, Davis, Thomas G.R., additional, Kohnle, Ian C., additional, Pope, Hans W., additional, Allen, Peter M., additional, Olander, Kira E., additional, Iracheta-Vellve, Arvin, additional, Doench, John G., additional, Haining, W. Nicholas, additional, Yates, Kathleen B., additional, and Manguso, Robert T., additional

Published
2021
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32. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target

Author

Manguso, Robert T., Pope, Hans W., Zimmer, Margaret D., Brown, Flavian D., Yates, Kathleen B., Miller, Brian C., Collins, Natalie B., Bi, Kevin, LaFleur, Martin W., Juneja, Vikram R., Weiss, Sarah A., Lo, Jennifer, Fisher, David E., Miao, Diana, Van Allen, Eliezer, Root, David E., Sharpe, Arlene H., Doench, John G., and Haining, W. Nicholas

Subjects
Genetic testing -- Analysis, Cancer treatment -- Methods -- Analysis, Cancer screening -- Analysis, Immunotherapy -- Analysis, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic screening approach using CRISPRCas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon- signalling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-B signalling, antigen presentation and the unfolded protein response. In addition, deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon--mediated effects on antigen presentation and growth suppression. In vivo genetic screens in tumour models can identify new immunotherapy targets in unanticipated pathways., Author(s): Robert T. Manguso [1, 2, 3]; Hans W. Pope [1, 3]; Margaret D. Zimmer [1, 3]; Flavian D. Brown [1, 2]; Kathleen B. Yates [1, 3]; Brian C. Miller [...]

Published
2017
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34. The PD-1 Pathway Regulates Development and Function of Memory CD8+ T Cells following Respiratory Viral Infection

Author

Pauken, Kristen E., primary, Godec, Jernej, additional, Odorizzi, Pamela M., additional, Brown, Keturah E., additional, Yates, Kathleen B., additional, Ngiow, Shin Foong, additional, Burke, Kelly P., additional, Maleri, Seth, additional, Grande, Shannon M., additional, Francisco, Loise M., additional, Ali, Mohammed-Alkhatim, additional, Imam, Sabrina, additional, Freeman, Gordon J., additional, Haining, W. Nicholas, additional, Wherry, E. John, additional, and Sharpe, Arlene H., additional

Published
2020
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35. Abstract PR6: Disrupting enhancers within the core epigenetic program of exhaustion improves T-cell responses and enhances tumor control

Author

Sen, Debattama R., primary, Weiss, Sarah A., additional, Miller, Brian C., additional, Tonnerre, Pierre, additional, Abosy, Rose Al, additional, Yates, Kathleen B., additional, Bi, Kevin, additional, Lafleur, Martin W., additional, Wolski, David, additional, Georg, Lauer, additional, Sharpe, Arlene H., additional, and Haining, W. Nicholas, additional

Published
2020
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36. Abstract A83: Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade

Author

Miller, Brian C., primary, Sen, Debattama R., additional, Abosy, Rose Al, additional, Bi, Kevin, additional, Virkud, Yamini, additional, LaFleur, Martin W., additional, Yates, Kathleen B., additional, Lako, Ana, additional, Felt, Kristen, additional, Naik, Girish S., additional, Manos, Michael, additional, Gjini, Evisa, additional, Ishizuka, Jeffrey J., additional, Hodi, F. Stephen, additional, Rodig, Scott J., additional, Sharpe, Arlene H., additional, and Haining, W. Nicholas, additional

Published
2020
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37. Abstract 2701: Functionally specialized subsets of exhausted CD8+ T cells mediate tumor control and differentially respond to checkpoint blockade

Author

Miller, Brian C., primary, Sen, Debattama R., additional, Abosy, Rose Al, additional, Bi, Kevin, additional, Virkud, Yamini V., additional, LaFleur, Martin W., additional, Yates, Kathleen B., additional, Lako, Ana, additional, Felt, Kristen, additional, Naik, Girish S., additional, Manos, Michael, additional, Gjini, Evisa, additional, Hodi, F. Stephen, additional, Rodig, Scott J., additional, Sharpe, Arlene H., additional, and Haining, W. Nicholas, additional

Published
2019
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38. Abstract A216: Functionally specialized subsets of exhausted CD8+ T-cells mediate tumor control and response to checkpoint blockade

Author

Sen, Debattama R., primary, Miller, Brian C., additional, Abosy, Rose Al, additional, Bi, Kevin, additional, LaFleur, Martin W., additional, Yates, Kathleen B., additional, Lako, Ana, additional, Felt, Kristen D., additional, Naik, Girish S., additional, Manos, Michael, additional, Gjini, Evisa, additional, Virkud, Yamini V., additional, Hodi, Stephen, additional, Rodig, Scott J., additional, Sharpe, Arlene H., additional, and Haining, W. Nicholas, additional

Published
2019
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39. Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade

Author

Ishizuka, Jeffrey J., primary, Manguso, Robert T., additional, Cheruiyot, Collins K., additional, Bi, Kevin, additional, Panda, Arpit, additional, Iracheta-Vellve, Arvin, additional, Miller, Brian C., additional, Du, Peter P., additional, Yates, Kathleen B., additional, Dubrot, Juan, additional, Buchumenski, Ilana, additional, Comstock, Dawn E., additional, Brown, Flavian D., additional, Ayer, Austin, additional, Kohnle, Ian C., additional, Pope, Hans W., additional, Zimmer, Margaret D., additional, Sen, Debattama R., additional, Lane-Reticker, Sarah K., additional, Robitschek, Emily J., additional, Griffin, Gabriel K., additional, Collins, Natalie B., additional, Long, Adrienne H., additional, Doench, John G., additional, Kozono, David, additional, Levanon, Erez Y., additional, and Haining, W. Nicholas, additional

Published
2018
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40. Epigenetic scars of CD8+T cell exhaustion persist after cure of chronic infection in humans

Author

Yates, Kathleen B., Tonnerre, Pierre, Martin, Genevieve E., Gerdemann, Ulrike, Al Abosy, Rose, Comstock, Dawn E., Weiss, Sarah A., Wolski, David, Tully, Damien C., Chung, Raymond T., Allen, Todd M., Kim, Arthur Y., Fidler, Sarah, Fox, Julie, Frater, John, Lauer, Georg M., Haining, W. Nicholas, and Sen, Debattama R.

Abstract

T cell exhaustion is an induced state of dysfunction that arises in response to chronic infection and cancer. Exhausted CD8+T cells acquire a distinct epigenetic state, but it is not known whether that chromatin landscape is fixed or plastic following the resolution of a chronic infection. Here we show that the epigenetic state of exhaustion is largely irreversible, even after curative therapy. Analysis of chromatin accessibility in HCV- and HIV-specific responses identifies a core epigenetic program of exhaustion in CD8+T cells, which undergoes only limited remodeling before and after resolution of infection. Moreover, canonical features of exhaustion, including super-enhancers near the genes TOXand HIF1A, remain ‘epigenetically scarred.’ T cell exhaustion is therefore a conserved epigenetic state that becomes fixed and persists independent of chronic antigen stimulation and inflammation. Therapeutic efforts to reverse T cell exhaustion may require new approaches that increase the epigenetic plasticity of exhausted T cells.

Published
2021
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42. Targeted reconstruction of T cell receptor sequence from single cell RNA-seq links CDR3 length to T cell differentiation state

Author

Afik, Shaked, primary, Yates, Kathleen B., additional, Bi, Kevin, additional, Darko, Samuel, additional, Godec, Jernej, additional, Gerdemann, Ulrike, additional, Swadling, Leo, additional, Douek, Daniel C., additional, Klenerman, Paul, additional, Barnes, Eleanor J., additional, Sharpe, Arlene H., additional, Haining, W. Nicholas, additional, and Yosef, Nir, additional

Published
2017
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43. Abstract 1019: In vivo CRISPR screening identifies Ptpn2 as a target for cancer immunotherapy

Author

Manguso, Robert T., primary, Pope, Hans W., additional, Zimmer, Margaret D., additional, Brown, Flavian D., additional, Yates, Kathleen B., additional, Miller, Brian C., additional, Collins, Natalie B., additional, Bi, Kevin, additional, Lafleur, Martin W., additional, Juneja, Vikram R., additional, Weiss, Sarah A., additional, Fisher, David E., additional, Root, David E., additional, Sharpe, Arlene H., additional, Doench, John G., additional, and Haining, W Nicholas, additional

Published
2017
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44. Vaccine-Elicited CD4 T Cells Induce Immunopathology Following Chronic LCMV Infection

Author

Penaloza-MacMaster, Pablo, Barber, Daniel L., Wherry, E. John, Provine, Nicholas M., Teigler, Jeffrey E., Parenteau, Lily, Blackmore, Stephen, Borducchi, Erica N., Larocca, Rafael A., Yates, Kathleen B., Shen, Hao, Haining, W. Nicholas, Sommerstein, Rami, Pinschewer, Daniel D., Ahmed, Rafi, and Barouch, Dan. H.

Subjects
CD4-Positive T-Lymphocytes, Inflammation, Multiple Organ Failure, Vaccination, Epitopes, T-Lymphocyte, Viral Vaccines, Adaptive Immunity, CD8-Positive T-Lymphocytes, Viral Load, Antibodies, Viral, Virus Replication, Article, Mice, Inbred C57BL, Immune System Diseases, Animals, Arenaviridae Infections, Cytokines, Lymphocytic choriomeningitis virus, Antigens, Viral, Immunologic Memory
Abstract

CD4 T cells promote innate and adaptive immune responses, but how vaccine-elicited CD4 T cells contribute to immune protection remains unclear. Here we evaluated whether induction of virus-specific CD4 T cells by vaccination would protect mice against infection with chronic lymphocytic choriomeningitis virus (LCMV). Immunization with vaccines that selectively induced CD4 T cell responses resulted in catastrophic inflammation and mortality following challenge with a persistent strain of LCMV. Immunopathology required antigen-specific CD4 T cells and was associated with a cytokine storm, generalized inflammation, and multi-organ system failure. Virus-specific CD8 T cells or antibodies abrogated the pathology. These data demonstrate that vaccine-elicited CD4 T cells in the absence of effective antiviral immune responses can trigger lethal immunopathology.

Published
2015

45. PTPN2 regulates the generation of exhausted CD8+T cell subpopulations and restrains tumor immunity

Author

LaFleur, Martin W., Nguyen, Thao H., Coxe, Matthew A., Miller, Brian C., Yates, Kathleen B., Gillis, Jacob E., Sen, Debattama R., Gaudiano, Emily F., Al Abosy, Rose, Freeman, Gordon J., Haining, W. Nicholas, and Sharpe, Arlene H.

Abstract

CD8+T cell exhaustion is a state of dysfunction acquired in chronic viral infection and cancer, characterized by the formation of Slamf6+progenitor exhausted and Tim-3+terminally exhausted subpopulations through unknown mechanisms. Here we establish the phosphatase PTPN2 as a new regulator of the differentiation of the terminally exhausted subpopulation that functions by attenuating type 1 interferon signaling. Deletion of Ptpn2in CD8+T cells increased the generation, proliferative capacity and cytotoxicity of Tim-3+cells without altering Slamf6+numbers during lymphocytic choriomeningitis virus clone 13 infection. Likewise, Ptpn2deletion in CD8+T cells enhanced Tim-3+anti-tumor responses and improved tumor control. Deletion of Ptpn2throughout the immune system resulted in MC38 tumor clearance and improved programmed cell death-1 checkpoint blockade responses to B16 tumors. Our results indicate that increasing the number of cytotoxic Tim-3+CD8+T cells can promote effective anti-tumor immunity and implicate PTPN2 in immune cells as an attractive cancer immunotherapy target.

Published
2019
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46. Immediate Dysfunction of Vaccine-Elicited CD8+ T Cells Primed in the Absence of CD4+ T Cells

Author

Provine, Nicholas M., primary, Larocca, Rafael A., additional, Aid, Malika, additional, Penaloza-MacMaster, Pablo, additional, Badamchi-Zadeh, Alexander, additional, Borducchi, Erica N., additional, Yates, Kathleen B., additional, Abbink, Peter, additional, Kirilova, Marinela, additional, Ng’ang’a, David, additional, Bramson, Jonathan, additional, Haining, W. Nicholas, additional, and Barouch, Dan H., additional

Published
2016
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47. Targeted reconstruction of T cell receptor sequence from single cell RNA-sequencing links CDR3 length to T cell differentiation state

Author

Afik, Shaked, primary, Yates, Kathleen B., additional, Bi, Kevin, additional, Darko, Samuel, additional, Godec, Jernej, additional, Gerdemann, Ulrike, additional, Swadling, Leo, additional, Douek, Daniel C., additional, Klenerman, Paul, additional, Barnes, Eleanor J., additional, Sharpe, Arlene H., additional, Haining, W. Nicholas, additional, and Yosef, Nir, additional

Published
2016
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48. Subsets of exhausted CD8+T cells differentially mediate tumor control and respond to checkpoint blockade

Author

Miller, Brian C., Sen, Debattama R., Al Abosy, Rose, Bi, Kevin, Virkud, Yamini V., LaFleur, Martin W., Yates, Kathleen B., Lako, Ana, Felt, Kristen, Naik, Girish S., Manos, Michael, Gjini, Evisa, Kuchroo, Juhi R., Ishizuka, Jeffrey J., Collier, Jenna L., Griffin, Gabriel K., Maleri, Seth, Comstock, Dawn E., Weiss, Sarah A., Brown, Flavian D., Panda, Arpit, Zimmer, Margaret D., Manguso, Robert T., Hodi, F. Stephen, Rodig, Scott J., Sharpe, Arlene H., and Haining, W. Nicholas

Abstract

T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1 (anti-PD-1) reinvigorates T cells are not fully understood. Here we show that such therapy acts on a specific subpopulation of exhausted CD8+tumor-infiltrating lymphocytes (TILs). Dysfunctional CD8+TILs possess canonical epigenetic and transcriptional features of exhaustion that mirror those seen in chronic viral infection. Exhausted CD8+TILs include a subpopulation of ‘progenitor exhausted’ cells that retain polyfunctionality, persist long term and differentiate into ‘terminally exhausted’ TILs. Consequently, progenitor exhausted CD8+TILs are better able to control tumor growth than are terminally exhausted T cells. Progenitor exhausted TILs can respond to anti-PD-1 therapy, but terminally exhausted TILs cannot. Patients with melanoma who have a higher percentage of progenitor exhausted cells experience a longer duration of response to checkpoint-blockade therapy. Thus, approaches to expand the population of progenitor exhausted CD8+T cells might be an important component of improving the response to checkpoint blockade.

Published
2019
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49. The Transcription Factor BATF Controls CD8+ T Cell Effector Differentiation

Author

Barnitz, R. Anthony, primary, Kurachi, Makoto, additional, Lemieux, Madeleine E., additional, Yosef, Nir, additional, DiIorio, Michael A., additional, Yates, Kathleen B., additional, Godec, Jernej, additional, Odorizzi, Pamela, additional, Regev, Aviv, additional, Wherry, E. John, additional, and Nicholas Haining, W., additional

Published
2013
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50. Protocol for in vivoCRISPR screening using selective CRISPR antigen removal lentiviral vectors

Author

Lane-Reticker, Sarah Kate, Kessler, Emily A., Muscato, Audrey J., Kim, Sarah Y., Doench, John G., Yates, Kathleen B., Manguso, Robert T., and Dubrot, Juan

Abstract

Recognition of Cas9 and other proteins encoded in delivery vectors has limited CRISPR technology in vivo. Here, we present a protocol for genome engineering using selective CRISPR antigen removal (SCAR) lentiviral vectors in Renca mouse model. This protocol describes how to conduct an in vivogenetic screen with a sgRNA library and SCAR vectors that can be applied to different cell lines and contexts.

Published
2023
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