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1. Distinguishing features of long COVID identified through immune profiling

Author

Klein, Jon, Wood, Jamie, Jaycox, Jillian R., Dhodapkar, Rahul M., Lu, Peiwen, Gehlhausen, Jeff R., Tabachnikova, Alexandra, Greene, Kerrie, Tabacof, Laura, Malik, Amyn A., Silva Monteiro, Valter, Silva, Julio, Kamath, Kathy, Zhang, Minlu, Dhal, Abhilash, Ott, Isabel M., Valle, Gabrielee, Peña-Hernández, Mario, Mao, Tianyang, Bhattacharjee, Bornali, Takahashi, Takehiro, Lucas, Carolina, Song, Eric, McCarthy, Dayna, Breyman, Erica, Tosto-Mancuso, Jenna, Dai, Yile, Perotti, Emily, Akduman, Koray, Tzeng, Tiffany J., Xu, Lan, Geraghty, Anna C., Monje, Michelle, Yildirim, Inci, Shon, John, Medzhitov, Ruslan, Lutchmansingh, Denyse, Possick, Jennifer D., Kaminski, Naftali, Omer, Saad B., Krumholz, Harlan M., Guan, Leying, Dela Cruz, Charles S., van Dijk, David, Ring, Aaron M., Putrino, David, and Iwasaki, Akiko

Published
2023
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2. Intratumoral dendritic cell–CD4+ T helper cell niches enable CD8+ T cell differentiation following PD-1 blockade in hepatocellular carcinoma

Author

Magen, Assaf, Hamon, Pauline, Fiaschi, Nathalie, Soong, Brian Y., Park, Matthew D., Mattiuz, Raphaël, Humblin, Etienne, Troncoso, Leanna, D’souza, Darwin, Dawson, Travis, Kim, Joel, Hamel, Steven, Buckup, Mark, Chang, Christie, Tabachnikova, Alexandra, Schwartz, Hara, Malissen, Nausicaa, Lavin, Yonit, Soares-Schanoski, Alessandra, Giotti, Bruno, Hegde, Samarth, Ioannou, Giorgio, Gonzalez-Kozlova, Edgar, Hennequin, Clotilde, Le Berichel, Jessica, Zhao, Zhen, Ward, Stephen C., Fiel, Isabel, Kou, Baijun, Dobosz, Michael, Li, Lianjie, Adler, Christina, Ni, Min, Wei, Yi, Wang, Wei, Atwal, Gurinder S., Kundu, Kunal, Cygan, Kamil J., Tsankov, Alexander M., Rahman, Adeeb, Price, Colles, Fernandez, Nicolas, He, Jiang, Gupta, Namita T., Kim-Schulze, Seunghee, Gnjatic, Sacha, Kenigsberg, Ephraim, Deering, Raquel P., Schwartz, Myron, Marron, Thomas U., Thurston, Gavin, Kamphorst, Alice O., and Merad, Miriam

Published
2023
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3. Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation

Author

Fernández-Castañeda, Anthony, Lu, Peiwen, Geraghty, Anna C., Song, Eric, Lee, Myoung-Hwa, Wood, Jamie, O’Dea, Michael R., Dutton, Selena, Shamardani, Kiarash, Nwangwu, Kamsi, Mancusi, Rebecca, Yalçın, Belgin, Taylor, Kathryn R., Acosta-Alvarez, Lehi, Malacon, Karen, Keough, Michael B., Ni, Lijun, Woo, Pamelyn J., Contreras-Esquivel, Daniel, Toland, Angus Martin Shaw, Gehlhausen, Jeff R., Klein, Jon, Takahashi, Takehiro, Silva, Julio, Israelow, Benjamin, Lucas, Carolina, Mao, Tianyang, Peña-Hernández, Mario A., Tabachnikova, Alexandra, Homer, Robert J., Tabacof, Laura, Tosto-Mancuso, Jenna, Breyman, Erica, Kontorovich, Amy, McCarthy, Dayna, Quezado, Martha, Vogel, Hannes, Hefti, Marco M., Perl, Daniel P., Liddelow, Shane, Folkerth, Rebecca, Putrino, David, Nath, Avindra, Iwasaki, Akiko, and Monje, Michelle

Published
2022
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4. Single-cell analysis of human non-small cell lung cancer lesions refines tumor classification and patient stratification

Author

Leader, Andrew M., Grout, John A., Maier, Barbara B., Nabet, Barzin Y., Park, Matthew D., Tabachnikova, Alexandra, Chang, Christie, Walker, Laura, Lansky, Alona, Le Berichel, Jessica, Troncoso, Leanna, Malissen, Nausicaa, Davila, Melanie, Martin, Jerome C., Magri, Giuliana, Tuballes, Kevin, Zhao, Zhen, Petralia, Francesca, Samstein, Robert, D’Amore, Natalie Roy, Thurston, Gavin, Kamphorst, Alice O., Wolf, Andrea, Flores, Raja, Wang, Pei, Müller, Sören, Mellman, Ira, Beasley, Mary Beth, Salmon, Hélène, Rahman, Adeeb H., Marron, Thomas U., Kenigsberg, Ephraim, and Merad, Miriam

Published
2021
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5. Impact of circulating SARS-CoV-2 variants on mRNA vaccine-induced immunity

Author

Lucas, Carolina, Vogels, Chantal B. F., Yildirim, Inci, Rothman, Jessica E., Lu, Peiwen, Monteiro, Valter, Gehlhausen, Jeff R., Campbell, Melissa, Silva, Julio, Tabachnikova, Alexandra, Peña-Hernandez, Mario A., Muenker, M. Catherine, Breban, Mallery I., Fauver, Joseph R., Mohanty, Subhasis, Huang, Jiefang, Shaw, Albert C., Ko, Albert I., Omer, Saad B., Grubaugh, Nathan D., and Iwasaki, Akiko

Published
2021
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6. Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells

Author

Casanova-Acebes, María, Dalla, Erica, Leader, Andrew M., LeBerichel, Jessica, Nikolic, Jovan, Morales, Blanca M., Brown, Markus, Chang, Christie, Troncoso, Leanna, Chen, Steven T., Sastre-Perona, Ana, Park, Matthew D., Tabachnikova, Alexandra, Dhainaut, Maxime, Hamon, Pauline, Maier, Barbara, and Sawai, Catherine M.

Subjects
Lung cancer, Non-small cell -- Development and progression, Macrophages -- Health aspects, Cancer cells -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Macrophages have a key role in shaping the tumour microenvironment (TME), tumour immunity and response to immunotherapy, which makes them an important target for cancer treatment.sup.1,2. However, modulating macrophages has proved extremely difficult, as we still lack a complete understanding of the molecular and functional diversity of the tumour macrophage compartment. Macrophages arise from two distinct lineages. Tissue-resident macrophages self-renew locally, independent of adult haematopoiesis.sup.3-5, whereas short-lived monocyte-derived macrophages arise from adult haematopoietic stem cells, and accumulate mostly in inflamed lesions.sup.1. How these macrophage lineages contribute to the TME and cancer progression remains unclear. To explore the diversity of the macrophage compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we performed single-cell RNA sequencing of tumour-associated leukocytes. We identified distinct populations of macrophages that were enriched in human and mouse lung tumours. Using lineage tracing, we discovered that these macrophage populations differ in origin and have a distinct temporal and spatial distribution in the TME. Tissue-resident macrophages accumulate close to tumour cells early during tumour formation to promote epithelial-mesenchymal transition and invasiveness in tumour cells, and they also induce a potent regulatory T cell response that protects tumour cells from adaptive immunity. Depletion of tissue-resident macrophages reduced the numbers and altered the phenotype of regulatory T cells, promoted the accumulation of CD8.sup.+ T cells and reduced tumour invasiveness and growth. During tumour growth, tissue-resident macrophages became redistributed at the periphery of the TME, which becomes dominated by monocyte-derived macrophages in both mouse and human NSCLC. This study identifies the contribution of tissue-resident macrophages to early lung cancer and establishes them as a target for the prevention and treatment of early lung cancer lesions. Single-cell RNA sequencing and imaging of macrophages in human non-small cell lung cancer and in a mouse model of lung adenocarcinoma show that tissue-resident macrophages have a key role in early tumour progression., Author(s): María Casanova-Acebes [sup.1] [sup.2] [sup.3] [sup.19] , Erica Dalla [sup.4] [sup.5] [sup.6] [sup.7] , Andrew M. Leader [sup.1] [sup.2] [sup.3] , Jessica LeBerichel [sup.1] [sup.2] [sup.3] , Jovan Nikolic [...]

Published
2021
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7. BRAFV600E-induced senescence drives Langerhans cell histiocytosis pathophysiology

Author

Bigenwald, Camille, Le Berichel, Jessica, Wilk, C. Matthias, Chakraborty, Rikhia, Chen, Steven T., Tabachnikova, Alexandra, Mancusi, Rebecca, Abhyankar, Harshal, Casanova-Acebes, Maria, Laface, Ilaria, Akturk, Guray, Jobson, Jenielle, Karoulia, Zoi, Martin, Jerome C., Grout, John, Rafiei, Anahita, Lin, Howard, Manz, Markus G., Baccarini, Alessia, Poulikakos, Poulikos I., Brown, Brian D., Gnjatic, Sacha, Lujambio, Amaia, McClain, Kenneth L., Picarsic, Jennifer, Allen, Carl E., and Merad, Miriam

Published
2021
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8. Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children

Author

Beckmann, Noam D., Comella, Phillip H., Cheng, Esther, Lepow, Lauren, Beckmann, Aviva G., Tyler, Scott R., Mouskas, Konstantinos, Simons, Nicole W., Hoffman, Gabriel E., Francoeur, Nancy J., Del Valle, Diane Marie, Kang, Gurpawan, Do, Anh, Moya, Emily, Wilkins, Lillian, Le Berichel, Jessica, Chang, Christie, Marvin, Robert, Calorossi, Sharlene, Lansky, Alona, Walker, Laura, Yi, Nancy, Yu, Alex, Chung, Jonathan, Hartnett, Matthew, Eaton, Melody, Hatem, Sandra, Jamal, Hajra, Akyatan, Alara, Tabachnikova, Alexandra, Liharska, Lora E., Cotter, Liam, Fennessy, Brian, Vaid, Akhil, Barturen, Guillermo, Shah, Hardik, Wang, Ying-chih, Sridhar, Shwetha Hara, Soto, Juan, Bose, Swaroop, Madrid, Kent, Ellis, Ethan, Merzier, Elyze, Vlachos, Konstantinos, Fishman, Nataly, Tin, Manying, Smith, Melissa, Xie, Hui, Patel, Manishkumar, Nie, Kai, Argueta, Kimberly, Harris, Jocelyn, Karekar, Neha, Batchelor, Craig, Lacunza, Jose, Yishak, Mahlet, Tuballes, Kevin, Scott, Ieisha, Kumar, Arvind, Jaladanki, Suraj, Agashe, Charuta, Thompson, Ryan, Clark, Evan, Losic, Bojan, Peters, Lauren, Roussos, Panagiotis, Zhu, Jun, Wang, Wenhui, Kasarskis, Andrew, Glicksberg, Benjamin S., Nadkarni, Girish, Bogunovic, Dusan, Elaiho, Cordelia, Gangadharan, Sandeep, Ofori-Amanfo, George, Alesso-Carra, Kasey, Onel, Kenan, Wilson, Karen M., Argmann, Carmen, Bunyavanich, Supinda, Alarcón-Riquelme, Marta E., Marron, Thomas U., Rahman, Adeeb, Kim-Schulze, Seunghee, Gnjatic, Sacha, Gelb, Bruce D., Merad, Miriam, Sebra, Robert, Schadt, Eric E., and Charney, Alexander W.

Published
2021
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9. No evidence of fetal defects or anti-syncytin-1 antibody induction following COVID-19 mRNA vaccination

Author

Lu-Culligan, Alice, primary, Tabachnikova, Alexandra, additional, Pérez-Then, Eddy, additional, Tokuyama, Maria, additional, Lee, Hannah J., additional, Lucas, Carolina, additional, Silva Monteiro, Valter, additional, Miric, Marija, additional, Brache, Vivian, additional, Cochon, Leila, additional, Muenker, M. Catherine, additional, Mohanty, Subhasis, additional, Huang, Jiefang, additional, Kang, Insoo, additional, Dela Cruz, Charles, additional, Farhadian, Shelli, additional, Campbell, Melissa, additional, Yildirim, Inci, additional, Shaw, Albert C., additional, Ma, Shuangge, additional, Vermund, Sten H., additional, Ko, Albert I., additional, Omer, Saad B., additional, and Iwasaki, Akiko, additional

Published
2022
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10. Shift of lung macrophage composition is associated with COVID-19 disease severity and recovery

Author

Chen, Steven T., Park, Matthew D., Del Valle, Diane Marie, Buckup, Mark, Tabachnikova, Alexandra, Simons, Nicole W., Mouskas, Konstantinos, Lee, Brian, Geanon, Daniel, D’Souza, Darwin, Dawson, Travis, Marvin, Robert, Nie, Kai, Thompson, Ryan C., Zhao, Zhen, LeBerichel, Jessica, Chang, Christie, Jamal, Hajra, Chaddha, Udit, Mathews, Kusum, Acquah, Samuel, Brown, Stacey-Ann, Reiss, Michelle, Harkin, Timothy, Feldmann, Marc, Powell, Charles A., Hook, Jaime L., Kim-Schulze, Seunghee, Rahman, Adeeb H., Brown, Brian D., Beckmann, Noam D., Gnjatic, Sacha, Kenigsberg, Ephraim, Charney, Alexander W., and Merad, Miriam

Subjects
Macrophages, Macrophages, Alveolar, COVID-19, Humans, Lung, Article, Monocytes
Abstract

Although it has been more than 2 years since the start of the coronavirus disease 2019 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, therapies to treat COVID-19 and other inflammatory diseases remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and mortality to develop tailored immunotherapy strategies to halt disease progression. We assembled the Mount Sinai COVID-19 Biobank, which was composed of almost 600 hospitalized patients followed longitudinally through the peak of the pandemic in 2020. Moderate disease and survival were associated with a stronger antigen presentation and effector T cell signature. In contrast, severe disease and death were associated with an altered antigen presentation signature, increased numbers of inflammatory immature myeloid cells, and extrafollicular activated B cells that have been previously associated with autoantibody formation. In severely ill patients with COVID-19, lung tissue-resident alveolar macrophages not only were drastically depleted but also had an altered antigen presentation signature, which coincided with an influx of inflammatory monocytes and monocyte-derived macrophages. In addition, we found that the size of the alveolar macrophage pool correlated with patient outcome and that alveolar macrophage numbers and functionality were restored to homeostasis in patients who recovered from COVID-19. These data suggest that local and systemic myeloid cell dysregulation are drivers of COVID-19 severity and modulation of alveolar macrophage numbers and activity in the lung may be a viable therapeutic strategy for the treatment of critical inflammatory lung diseases.

Published
2022

11. 685 Characterization of molecular and spatial diversity of macrophages in hepatocellular carcinoma

Author

Hamon, Pauline, primary, Magen, Assaf, additional, Kim, Joel, additional, Buckup, Mark, additional, Troncoso, Leanna, additional, Hamel, Steven, additional, Berichel, Jessica Le, additional, Barboy, Oren, additional, David, Eyal, additional, Tabachnikova, Alexandra, additional, Chang, Christie, additional, Zhao, Zhen, additional, Cohen, Merav, additional, Giladi, Amir, additional, Malissen, Nausicaa, additional, Desland, Fiona, additional, Amit, Ido, additional, Kenigsberg, Ephraim, additional, Schwartz, Myron, additional, Marron, Thomas, additional, and Merad, Miriam, additional

Published
2021
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12. Intratumoral dendritic cell–CD4+T helper cell niches enable CD8+T cell differentiation following PD-1 blockade in hepatocellular carcinoma

Author

Magen, Assaf, Hamon, Pauline, Fiaschi, Nathalie, Soong, Brian Y., Park, Matthew D., Mattiuz, Raphaël, Humblin, Etienne, Troncoso, Leanna, D’souza, Darwin, Dawson, Travis, Kim, Joel, Hamel, Steven, Buckup, Mark, Chang, Christie, Tabachnikova, Alexandra, Schwartz, Hara, Malissen, Nausicaa, Lavin, Yonit, Soares-Schanoski, Alessandra, Giotti, Bruno, Hegde, Samarth, Ioannou, Giorgio, Gonzalez-Kozlova, Edgar, Hennequin, Clotilde, Le Berichel, Jessica, Zhao, Zhen, Ward, Stephen C., Fiel, Isabel, Kou, Baijun, Dobosz, Michael, Li, Lianjie, Adler, Christina, Ni, Min, Wei, Yi, Wang, Wei, Atwal, Gurinder S., Kundu, Kunal, Cygan, Kamil J., Tsankov, Alexander M., Rahman, Adeeb, Price, Colles, Fernandez, Nicolas, He, Jiang, Gupta, Namita T., Kim-Schulze, Seunghee, Gnjatic, Sacha, Kenigsberg, Ephraim, Deering, Raquel P., Schwartz, Myron, Marron, Thomas U., Thurston, Gavin, Kamphorst, Alice O., and Merad, Miriam

Abstract

Despite no apparent defects in T cell priming and recruitment to tumors, a large subset of T cell rich tumors fail to respond to immune checkpoint blockade (ICB). We leveraged a neoadjuvant anti-PD-1 trial in patients with hepatocellular carcinoma (HCC), as well as additional samples collected from patients treated off-label, to explore correlates of response to ICB within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13+CH25H+IL-21+PD-1+CD4+T helper cells (“CXCL13+TH”) and Granzyme K+PD-1+effector-like CD8+T cells, whereas terminally exhausted CD39hiTOXhiPD-1hiCD8+T cells dominated in nonresponders. CD4+and CD8+T cell clones that expanded post-treatment were found in pretreatment biopsies. Notably, PD-1+TCF-1+(Progenitor-exhausted) CD8+T cells shared clones mainly with effector-like cells in responders or terminally exhausted cells in nonresponders, suggesting that local CD8+T cell differentiation occurs upon ICB. We found that these Progenitor CD8+T cells interact with CXCL13+THwithin cellular triads around dendritic cells enriched in maturation and regulatory molecules, or “mregDC”. These results suggest that discrete intratumoral niches that include mregDC and CXCL13+THcontrol the differentiation of tumor-specific Progenitor exhasuted CD8+T cells following ICB.

Published
2023
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13. Sampling the host response to SARS-CoV-2 in hospitals under siege

Author

Charney, Alexander W., Simons, Nicole W., Mouskas, Konstantinos, Lepow, Lauren, Cheng, Esther, Le Berichel, Jessica, Chang, Christie, Marvin, Robert, Del Valle, Diane Marie, Calorossi, Sharlene, Lansky, Alona, Walker, Laura, Patel, Manishkumar, Xie, Hui, Yi, Nancy, Yu, Alex, Kang, Gurpawan, Mendoza, Anthony, Liharska, Lora E., Moya, Emily, Hartnett, Matthew, Hatem, Sandra, Wilkins, Lillian, Eaton, Melody, Jamal, Hajra, Tuballes, Kevin, Chen, Steven T., Tabachnikova, Alexandra, Chung, Jonathan, Harris, Jocelyn, Batchelor, Craig, Lacunza, Jose, Yishak, Mahlet, Argueta, Kimberly, Karekar, Neha, Lee, Brian, Kelly, Geoffrey, Geanon, Daniel, Handler, Diana, Leech, John, Stefanos, Hiyab, Dawson, Travis, Scott, Ieisha, Francoeur, Nancy, Johnson, Jessica S., Vaid, Akhil, Glicksberg, Benjamin S., Nadkarni, Girish N., Schadt, Eric E., Gelb, Bruce D., Rahman, Adeeb, Sebra, Robert, Martin, Glenn, Agashe, Charuta, Agrawal, Priyal, Akyatan, Alara, Alesso-Carra, Kasey, Alibo, Eziwoma, Alvarez, Kelvin, Amabile, Angelo, Ascolillo, Steven, Bailey, Rasheed, Begani, Priya, Correra, Paloma Bravo, Brown, Stacey-Ann, Buckup, Mark, Burka, Larissa, Cambron, Lena, Carrara, Gina, Chang, Serena, Chien, Jonathan, Chowdhury, Mashkura, Bozkus, Cansu Cimen, Comella, Phillip, Cosgrove, Dana, Cossarini, Francesca, Cotter, Liam, Dave, Arpit, Dayal, Bheesham, Dhainaut, Maxime, Dornfeld, Rebecca, Dul, Katie, Eber, Nissan, Elaiho, Cordelia, Fabris, Frank, Faith, Jeremiah, Falci, Dominique, Feng, Susie, Fennessy, Brian, Fernandes, Marie, Gangadharan, Sandeep, Grabowska, Joanna, Gyimesi, Gavin, Hamdani, Maha, Herbinet, Manon, Herrera, Elva, Hochman, Arielle, Hoffman, Gabriel E., Hook, Jaime, Horta, Laila, Humblin, Etienne, Karim, Subha, Kim, Jessica, Lebovitch, Dannielle, Lee, Grace, Lee, Gyu Ho, Lee, Jacky, Leventhal, Mike, Lindblad, Katherine, Livanos, Alexandra, Machado, Rosalie, Mahmood, Zafar, Mar, Kelcey, Maskey, Shrisha, Matthews, Paul, Meckel, Katherine, Mehandru, Saurabh, Mercedes, Cynthia, Meyer, Dara, Mollaoglu, Gurkan, Morris, Sarah, Nie, Kai, Nisenholtz, Marjorie, Ofori-Amanfo, George, Onel, Kenan, Ounadjela, Merouane, Patel, Vishwendra, Pruitt, Cassandra, Rathi, Shivani, Redes, Jamie, Reyes-Torres, Ivan, Rodrigues, Alcina, Rodriguez, Alfonso, Roudko, Vladimir, Ruiz, Evelyn, Scalzo, Pearl, Silva, Pedro, Schanoski, Alessandra Soares, Straw, Meghan, Tabachnikova, Sasha, Teague, Collin, Upadhyaya, Bhaskar, Van Der Heide, Verena, Vaninov, Natalie, Wacker, Daniel, Walsh, Hadley, Wilk, C. Matthias, Wilson, Jessica, Wilson, Karen M., Xue, Li, Yeboah, Naa-akomaah, Young, Sabina, Zaks, Nina, Zha, Renyuan, Marron, Thomas, Beckmann, Noam, Kim-Schulze, Seunghee, Gnjatic, Sacha, and Merad, Miriam

Subjects
Siege, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), biology, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Host response, Sampling (statistics), General Medicine, biology.organism_classification, Virology, General Biochemistry, Genetics and Molecular Biology, Pandemic, Medicine, business, Betacoronavirus
Published
2020
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14. Author Correction: Sampling the host response to SARS-CoV-2 in hospitals under siege

Author

Charney, Alexander W., Simons, Nicole W., Mouskas, Konstantinos, Lepow, Lauren, Cheng, Esther, Le Berichel, Jessica, Chang, Christie, Marvin, Robert, Del Valle, Diane Marie, Calorossi, Sharlene, Lansky, Alona, Walker, Laura, Patel, Manishkumar, Xie, Hui, Yi, Nancy, Yu, Alex, Kang, Gurpawan, Mendoza, Anthony, Liharska, Lora E., Moya, Emily, Hartnett, Matthew, Hatem, Sandra, Wilkins, Lillian, Eaton, Melody, Jamal, Hajra, Tuballes, Kevin, Chen, Steven T., Tabachnikova, Alexandra, Chung, Jonathan, Harris, Jocelyn, Batchelor, Craig, Lacunza, Jose, Yishak, Mahlet, Argueta, Kimberly, Karekar, Neha, Lee, Brian, Kelly, Geoffrey, Geanon, Daniel, Handler, Diana, Leech, John, Stefanos, Hiyab, Dawson, Travis, Scott, Ieisha, Francoeur, Nancy, Johnson, Jessica S., Vaid, Akhil, Glicksberg, Benjamin S., Nadkarni, Girish N., Schadt, Eric E., Gelb, Bruce D., Rahman, Adeeb, Sebra, Robert, Martin, Glenn, Marron, Thomas, Beckmann, Noam, Kim-Schulze, Seunghee, Gnjatic, Sacha, and Merad, Miriam

Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41591-021-01247-3.

Published
2021
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15. Dendritic cells type 1 control the formation, maintenance, and function of tertiary lymphoid structures in cancer.

Author

Mattiuz R, Boumelha J, Hamon P, Le Berichel J, Vaidya A, Soong BY, Halasz L, Radkevich E, Kim HM, Park MD, Donne R, Troncoso L, D'Souza D, Kaiza ME, MacFawn IP, Belabed M, Mestrallet G, Humblin E, Merand R, Hennequin C, Ioannou G, Ozbey S, Figueiredo I, Hegde S, Tepper A, Merarda H, Nemeth E, Goldstein S, Reid AM, Noureddine M, Tabachnikova A, Ahmed J, Polydorides AD, Bhardwaj N, Lujambio A, Chen Z, Gonzalez Kozlova E, Kim-Schulze S, Brody JD, Schotsaert M, Moussion C, Gnjatic S, Sautès-Fridman C, Fridman WH, Roudko V, Brown BD, Marron TU, Cyster JG, Salmon H, Bruno TC, Joshi NS, Kamphorst AO, and Merad M

Abstract

Tertiary lymphoid structures (TLS) are organized immune cell aggregates that arise in chronic inflammatory conditions. In cancer, TLS are associated with better prognosis and enhanced response to immunotherapy, making these structures attractive therapeutic targets. However, the mechanisms regulating TLS formation and maintenance in cancer are incompletely understood. Using spatial transcriptomics and multiplex imaging across various human tumors, we found an enrichment of mature dendritic cells (DC) expressing high levels of CCR7 in TLS, prompting us to investigate the role of DC in the formation and maintenance of TLS in solid tumors. To address this, we developed a novel murine model of non-small cell lung cancer (NSCLC) that forms mature TLS, containing B cell follicles with germinal centers and T cell zones with T follicular helper cells (T FH ) and TCF1 + PD-1 + progenitor exhausted CD8 + T cells (Tpex). Here we show that, during the early stages of tumor development, TLS formation relies on IFNγ-driven maturation of the conventional DC type 1 (cDC1) subset, their migration to tumor-draining lymph nodes (tdLN), and recruitment of activated T cells to the tumor site. As tumors progress, TLS maintenance becomes independent of T cell egress from tdLN, coinciding with a significant reduction of cDC1 migration to tdLN. Instead, mature cDC1 accumulate within intratumoral CCR7 ligand-enriched stromal hubs. Notably, timed depletion of cDC1 or disruption of their migration to these stromal hubs after TLS are formed alters TLS maintenance. Importantly, we found that cDC1-mediated antigen presentation to both CD4 + and CD8 + T cells and intact CD40 signaling, is critical for the maintenance of TLS, the preservation of the T FH cell pool, the formation of germinal center and the production of tumor-specific IgG antibodies. These findings underscore the key role of mature cDC1 in establishing and maintaining functional TLS within tumor lesions and highlight the potential for cDC1-targeting therapies as a promising strategy to enhance TLS function and improve anti-tumor immunity in patients with cancer.

Published
2024
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16. Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain.

Author

Fernández-Castañeda A, Lu P, Geraghty AC, Song E, Lee MH, Wood J, Yalçın B, Taylor KR, Dutton S, Acosta-Alvarez L, Ni L, Contreras-Esquivel D, Gehlhausen JR, Klein J, Lucas C, Mao T, Silva J, Peña-Hernández MA, Tabachnikova A, Takahashi T, Tabacof L, Tosto-Mancuso J, Breyman E, Kontorovich A, McCarthy D, Quezado M, Hefti M, Perl D, Folkerth R, Putrino D, Nath A, Iwasaki A, and Monje M

Abstract

Survivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing and memory. This long-COVID cognitive syndrome shares many features with the syndrome of cancer therapy-related cognitive impairment (CRCI). Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection. Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection - without neuroinvasion - and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function. Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.

Published
2022
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