[en] Antigen processing and presentation (APP) is essential for adaptive immunosurveillance. We uncover a mechanism whereby activated T cell-derived extracellular vesicles (ATEVs) drive a positive feedback loop that enhances antigen presentation and immune responses in normal physiology and cancer. ATEV-induced immunogenicity relies on extracellular vesicular double-stranded DNA (EVDNA), which is notably abundant and primarily composed of genomic DNA enriched in immune-related genes, including those encoding APP machinery. Mechanistically, granzyme B (Gzmb) packaged by ATEVs disrupts the nuclear envelope of recipient cells, facilitating intranuclear transfer and subsequent transient expression of EVDNA encoding APP genes. DNase treatment removes most AT-EVDNA, abrogating APP upregulation and thus T cell activation and recruitment to tumors. Notably, ATEVs hold promise as an acellular immunotherapy, restoring APP and synergizing with checkpoint blockade in immunotherapy-refractory tumors. Collectively, our findings uncover a mechanism of transient, non-viral gene delivery by ATEVs that boosts APP and anti-tumor immunity while limiting autoimmunity.
Disciplines :
Oncology
Author, co-author :
Hu, Mengying; Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA, Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
Liu, Di-Ao; Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
Wortzel, Inbal; Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
Collier, Paul; Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA
Nelson, Theodore M; Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA
Foox, Jonathan; Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA
Zhong, Guojie; Department of Systems Biology, Columbia University, New York, NY, USA
Tobias, Gabriel; Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
Asao, Tetsuhiko; Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA, Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA, Department of Respiratory Medicine, Juntendo University, Tokyo, Japan
Bojmar, Linda; Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
Kenific, Candia M; Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
Wang, Gang; Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
Caielli, Simone; Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA
Wan, Zurong; Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA
Qureshy, Sarah; Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
Reed, Max; Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
Piszczatowski, Richard; Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
Ravisankar, Purnima; Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA
Brown, Julia A; Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA
Xiong, Sihan; Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
Wang, Huajuan; Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
Lauritzen, Pernille; Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
Aylon, Yael; Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel
Molina, Henrik; Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA
Jarnagin, William R; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Oren, Moshe; Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel
Stanger, Ben Z; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Bui, Jack; Department of Pathology, University of California, San Diego, La Jolla, CA, USA
Bergers, Gabriele; Laboratory of Tumor Microenvironment and Therapeutic Resistance, KU Leuven, Leuven, Belgium
Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire
Grandgenett, Paul M; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
Hollingsworth, Michael A; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
Tuveson, David; Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY 11724, USA
Boudreau, Nancy; Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
Bromberg, Jacqueline; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Kelsen, David; Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Jones, David R; Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Santambrogio, Laura; Department of Radiation Oncology, Weill Cornell School of Medicine, New York, NY, USA
Zeng, Melody Y; Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA
Pascual, Virginia; Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA
Kim, Han Sang; Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA, Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
Mason, Christopher E; Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA
Zhang, Haiying; Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address: haz2005@med.cornell.edu
Matei, Irina R; Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address: irm2224@med.cornell.edu
Lyden, David; Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address: dcl2001@med.cornell.edu
Sohn Conference Foundation NIGMS - National Institute of General Medical Sciences NIH. NCI - National Institutes of Health. National Cancer Institute Hartwell Foundation NIAID - National Institute of Allergy and Infectious Diseases
Yang, K., Halima, A., Chan, T.A., Antigen presentation in cancer—mechanisms and clinical implications for immunotherapy. Nat. Rev. Clin. Oncol. 20 (2023), 604–623.
Jhunjhunwala, S., Hammer, C., Delamarre, L., Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. Nat. Rev. Cancer 21 (2021), 298–312.
Hodi, F.S., O'day, S.J., McDermott, D.F., Weber, R.W., Sosman, J.A., Haanen, J.B., Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J.C., et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. Overseas. Ed. 363 (2010), 711–723.
Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J.J., Cowey, C.L., Lao, C.D., Schadendorf, D., Dummer, R., Smylie, M., Rutkowski, P., et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373 (2015), 23–34.
Yamamoto, K., Venida, A., Yano, J., Biancur, D.E., Kakiuchi, M., Gupta, S., Sohn, A.S.W., Mukhopadhyay, S., Lin, E.Y., Parker, S.J., et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature 581 (2020), 100–105.
Fangazio, M., Ladewig, E., Gomez, K., Garcia-Ibanez, L., Kumar, R., Teruya-Feldstein, J., Rossi, D., Filip, I., Pan-Hammarström, Q., Inghirami, G., et al. Genetic mechanisms of HLA-I loss and immune escape in diffuse large B cell lymphoma. Proc. Natl. Acad. Sci. USA, 118, 2021, e2104504118.
Beyaz, S., Chung, C., Mou, H., Bauer-Rowe, K.E., Xifaras, M.E., Ergin, I., Dohnalova, L., Biton, M., Shekhar, K., Eskiocak, O., et al. Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis. Cell Stem Cell 28 (2021), 1922–1935.e5.
Hu, Q., Ye, Y., Chan, L.-C., Li, Y., Liang, K., Lin, A., Egranov, S.D., Zhang, Y., Xia, W., Gong, J., et al. Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression. Nat. Immunol. 20 (2019), 835–851.
Mahadevan, N.R., Knelson, E.H., Wolff, J.O., Vajdi, A., Saigí, M., Campisi, M., Hong, D., Thai, T.C., Piel, B., Han, S., et al. Intrinsic immunogenicity of small cell lung carcinoma revealed by its cellular plasticity. Cancer Discov. 11 (2021), 1952–1969.
Burr, M.L., Sparbier, C.E., Chan, K.L., Chan, Y.-C., Kersbergen, A., Lam, E.Y.N., Azidis-Yates, E., Vassiliadis, D., Bell, C.C., Gilan, O., et al. An evolutionarily conserved function of polycomb silences the MHC class I antigen presentation pathway and enables immune evasion in cancer. Cancer Cell 36 (2019), 385–401.e8.
Hangai, S., Ao, T., Kimura, Y., Matsuki, K., Kawamura, T., Negishi, H., Nishio, J., Kodama, T., Taniguchi, T., Yanai, H., PGE2 induced in and released by dying cells functions as an inhibitory DAMP. Proc. Natl. Acad. Sci. USA 113 (2016), 3844–3849.
Gabrilovich, D.I., Chen, H.L., Girgis, K.R., Cunningham, H.T., Meny, G.M., Nadaf, S., Kavanaugh, D., Carbone, D.P., Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat. Med. 2 (1996), 1096–1103.
Papaspyridonos, M., Matei, I., Huang, Y., do Rosario Andre, M., Brazier-Mitouart, H., Waite, J.C., Chan, A.S., Kalter, J., Ramos, I., Wu, Q., et al. Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation. Nat. Commun., 6, 2015, 6840.
Herber, D.L., Cao, W., Nefedova, Y., Novitskiy, S.V., Nagaraj, S., Tyurin, V.A., Corzo, A., Cho, H.-I., Celis, E., Lennox, B., et al. Lipid accumulation and dendritic cell dysfunction in cancer. Nat. Med. 16 (2010), 880–886.
Gao, J., Shi, L.Z., Zhao, H., Chen, J., Xiong, L., He, Q., Chen, T., Roszik, J., Bernatchez, C., Woodman, S.E., et al. Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell 167 (2016), 397–404.e9.
Zaretsky, J.M., Garcia-Diaz, A., Shin, D.S., Escuin-Ordinas, H., Hugo, W., Hu-Lieskovan, S., Torrejon, D.Y., Abril-Rodriguez, G., Sandoval, S., Barthly, L., et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375 (2016), 819–829.
Gocher, A.M., Workman, C.J., Vignali, D.A.A., Interferon-γ: teammate or opponent in the tumour microenvironment?. Nat. Rev. Immunol. 22 (2022), 158–172.
Giannopoulos, A., Constantinides, C., Fokaeas, E., Stravodimos, C., Giannopoulou, M., Kyroudi, A., Gounaris, A., The immunomodulating effect of interferon-γ intravesical instillations in preventing bladder cancer recurrence. Clin. Cancer Res. 9 (2003), 5550–5558.
Windbichler, G.H., Hausmaninger, H., Stummvoll, W., Graf, A.H., Kainz, C., Lahodny, J., Denison, U., Müller-Holzner, E., Marth, C., Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase III trial. Br. J. Cancer 82 (2000), 1138–1144.
Alberts, D.S., Marth, C., Alvarez, R.D., Johnson, G., Bidzinski, M., Kardatzke, D.R., Bradford, W.Z., Loutit, J., Kirn, D.H., Clouser, M.C., et al. Randomized phase 3 trial of interferon gamma-1b plus standard carboplatin/paclitaxel versus carboplatin/paclitaxel alone for first-line treatment of advanced ovarian and primary peritoneal carcinomas: results from a prospectively designed analysis of progression-free survival. Gynecol. Oncol. 109 (2008), 174–181.
Hu, M., Kenific, C.M., Boudreau, N., Lyden, D., Tumor-derived Nanoseeds Condition the Soil for Metastatic Organotropism. 2023, Elsevier, 70–82.
Thakur, B.K., Zhang, H., Becker, A., Matei, I., Huang, Y., Costa-Silva, B., Zheng, Y., Hoshino, A., Brazier, H., Xiang, J., et al. Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res. 24 (2014), 766–769.
Sansone, P., Savini, C., Kurelac, I., Chang, Q., Amato, L.B., Strillacci, A., Stepanova, A., Iommarini, L., Mastroleo, C., Daly, L., et al. Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer. Proc. Natl. Acad. Sci. USA 114 (2017), E9066–E9075.
Wortzel, I., Seo, Y., Akano, I., Shaashua, L., Tobias, G.C., Hebert, J., Kim, K.-A., Kim, D., Dror, S., Liu, Y., et al. Unique structural configuration of EV-DNA primes Kupffer cell-mediated antitumor immunity to prevent metastatic progression. Nat. Cancer 5 (2024), 1815–1833.
Garcia, K.C., Teyton, L., Wilson, I.A., Structural basis of T cell recognition. Annu. Rev. Immunol. 17 (1999), 369–397.
Mantovani, A., Dinarello, C.A., Molgora, M., Garlanda, C., Interleukin-1 and related cytokines in the regulation of inflammation and immunity. Immunity 50 (2019), 778–795.
Vanderbeck, A., Maillard, I., Notch signaling at the crossroads of innate and adaptive immunity. J. Leukoc. Biol. 109 (2021), 535–548.
Pagliari, D., Cianci, R., Frosali, S., Landolfi, R., Cammarota, G., Newton, E.E., Pandolfi, F., The role of IL-15 in gastrointestinal diseases: a bridge between innate and adaptive immune response. Cytokine Growth Factor Rev. 24 (2013), 455–466.
Iwasaki, A., Medzhitov, R., Control of adaptive immunity by the innate immune system. Nat. Immunol. 16 (2015), 343–353.
Lanna, A., Vaz, B., D'Ambra, C., Valvo, S., Vuotto, C., Chiurchiù, V., Devine, O., Sanchez, M., Borsellino, G., Akbar, A.N., et al. An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory. Nat. Cell Biol. 24 (2022), 1461–1474.
Bojmar, L., Kim, H.S., Tobias, G.C., Pelissier Vatter, F.A., Lucotti, S., Gyan, K.E., Kenific, C.M., Wan, Z., Kim, K.-A., Kim, D., et al. Extracellular vesicle and particle isolation from human and murine cell lines, tissues, and bodily fluids. STAR Protoc., 2, 2021, 100225.
Hoshino, A., Kim, H.S., Bojmar, L., Gyan, K.E., Cioffi, M., Hernandez, J., Zambirinis, C.P., Rodrigues, G., Molina, H., Heissel, S., et al. Extracellular vesicle and particle biomarkers define multiple human cancers. Cell 182 (2020), 1044–1061.e18.
Gaidt, M.M., Rapino, F., Graf, T., Hornung, V., Modeling primary human monocytes with the trans–differentiation cell line BLaER1. Innate Immune Activation. Methods Mol. Biol. 1714 (2018), 57–66.
Wang, Y., Tiruthani, K., Li, S., Hu, M., Zhong, G., Tang, Y., Roy, S., Zhang, L., Tan, J., Liao, C., Liu, R., mRNA delivery of a bispecific single-domain antibody to polarize tumor-associated macrophages and synergize immunotherapy against liver malignancies. Adv. Mater., 33, 2021, 2007603.
Zhang, H., Freitas, D., Kim, H.S., Fabijanic, K., Li, Z., Chen, H., Mark, M.T., Molina, H., Martin, A.B., Bojmar, L., et al. Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation. Nat. Cell Biol. 20 (2018), 332–343.
Kalbasi, A., Ribas, A., Tumour-intrinsic resistance to immune checkpoint blockade. Nat. Rev. Immunol. 20 (2020), 25–39.
Wiklander, O.P.B., Nordin, J.Z., O'Loughlin, A., Gustafsson, Y., Corso, G., Mäger, I., Vader, P., Lee, Y., Sork, H., Seow, Y., et al. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J. Extracell. Vesicles, 4, 2015, 26316.
Qiao, L., Hu, S., Huang, K., Su, T., Li, Z., Vandergriff, A., Cores, J., Dinh, P.-U., Allen, T., Shen, D., et al. Tumor cell-derived exosomes home to their cells of origin and can be used as Trojan horses to deliver cancer drugs. Theranostics 10 (2020), 3474–3487.
Roland, C.L., Harken, A.H., Sarr, M.G., Barnett, C.C. Jr., ICAM-1 expression determines malignant potential of cancer. Surgery 141 (2007), 705–707.
Hayes, S.H., Seigel, G.M., Immunoreactivity of ICAM-1 in human tumors, metastases and normal tissues. Int. J. Clin. Exp. Pathol. 2 (2009), 553–560.
Leinwand, J., Miller, G., Regulation and modulation of antitumor immunity in pancreatic cancer. Nat. Immunol. 21 (2020), 1152–1159.
Li, J., Byrne, K.T., Yan, F., Yamazoe, T., Chen, Z., Baslan, T., Richman, L.P., Lin, J.H., Sun, Y.H., Rech, A.J., et al. Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy. Immunity 49 (2018), 178–193.e7.
Genoud, V., Marinari, E., Nikolaev, S.I., Castle, J.C., Bukur, V., Dietrich, P.-Y., Okada, H., Walker, P.R., Responsiveness to anti-PD-1 and anti-CTLA-4 immune checkpoint blockade in SB28 and GL261 mouse glioma models. OncoImmunology, 7, 2018, e1501137.
Arens, R., Scheeren, F.A., Genetic screening for novel regulators of immune checkpoint molecules. Trends Immunol. 41 (2020), 692–705.
Jorgovanovic, D., Song, M., Wang, L., Zhang, Y., Roles of IFN-γ in tumor progression and regression: a review. Biomark. Res., 8, 2020, 49.
Kobayashi, K.S., Van Den Elsen, P.J., NLRC5: a key regulator of MHC class I-dependent immune responses. Nat. Rev. Immunol. 12 (2012), 813–820.
Vijayan, S., Sidiq, T., Yousuf, S., van den Elsen, P.J., Kobayashi, K.S., Class I transactivator, NLRC5: a central player in the MHC class I pathway and cancer immune surveillance. Immunogenetics 71 (2019), 273–282.
Emming, S., Schroder, K., Tiered DNA sensors for escalating responses. Science 365 (2019), 1375–1376.
Temizoz, B., Kuroda, E., Ohata, K., Jounai, N., Ozasa, K., Kobiyama, K., Aoshi, T., Ishii, K.J., TLR9 and STING agonists synergistically induce innate and adaptive type-II IFN. Eur. J. Immunol. 45 (2015), 1159–1169.
Rathinam, V.A.K., Jiang, Z., Waggoner, S.N., Sharma, S., Cole, L.E., Waggoner, L., Vanaja, S.K., Monks, B.G., Ganesan, S., Latz, E., et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat. Immunol. 11 (2010), 395–402.
Tanaka, Y., Chen, Z.J., STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Sci. Signal., 5, 2012, ra20.
Santegoets, S.J.A.M., Turksma, A.W., Suhoski, M.M., Stam, A.G.M., Albelda, S.M., Hooijberg, E., Scheper, R.J., van den Eertwegh, A.J.M., Gerritsen, W.R., Powell, D.J. Jr., et al. IL-21 promotes the expansion of CD27+ CD28+ tumor infiltrating lymphocytes with high cytotoxic potential and low collateral expansion of regulatory T cells. J. Transl. Med., 11, 2013, 37.
Nurieva, R., Yang, X.O., Martinez, G., Zhang, Y., Panopoulos, A.D., Ma, L., Schluns, K., Tian, Q., Watowich, S.S., Jetten, A.M., Dong, C., Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448 (2007), 480–483.
Zhang, D., Beresford, P.J., Greenberg, A.H., Lieberman, J., Granzymes A and B directly cleave lamins and disrupt the nuclear lamina during granule-mediated cytolysis. Proc. Natl. Acad. Sci. USA 98 (2001), 5746–5751.
Boivin, W.A., Cooper, D.M., Hiebert, P.R., Granville, D.J., Intracellular versus extracellular granzyme B in immunity and disease. Lab. Invest. 89 (2009), 1195–1220.
Denais, C.M., Gilbert, R.M., Isermann, P., McGregor, A.L., Te Lindert, M., Weigelin, B., Davidson, P.M., Friedl, P., Wolf, K., Lammerding, J., Nuclear envelope rupture and repair during cancer cell migration. Science 352 (2016), 353–358.
Ivančić, D., Mir-Pedrol, J., Jaraba-Wallace, J., Rafel, N., Sanchez-Mejias, A., Güell, M., INSERT-seq enables high-resolution mapping of genomically integrated DNA using Nanopore sequencing. Genome Biol., 23, 2022, 227.
Hoshino, A., Costa-Silva, B., Shen, T.-L., Rodrigues, G., Hashimoto, A., Tesic Mark, M., Molina, H., Kohsaka, S., Di Giannatale, A., Ceder, S., et al. Tumour exosome integrins determine organotropic metastasis. Nature 527 (2015), 329–335.
González-Amaro, R., Sanchez-Madrid, F., Cell adhesion molecules: selectins and integrins. Crit. Rev. Immunol., 19, 1999, 389.
Torralba, D., Baixauli, F., Villarroya-Beltri, C., Fernández-Delgado, I., Latorre-Pellicer, A., Acín-Pérez, R., Martín-Cófreces, N.B., Jaso-Tamame, Á.L., Iborra, S., Jorge, I., et al. Priming of dendritic cells by DNA-containing extracellular vesicles from activated T cells through antigen-driven contacts. Nat. Commun., 9, 2018, 2658.
Diamond, J.M., Vanpouille-Box, C., Spada, S., Rudqvist, N.-P., Chapman, J.R., Ueberheide, B.M., Pilones, K.A., Sarfraz, Y., Formenti, S.C., Demaria, S., Exosomes shuttle TREX1-sensitive IFN-stimulatory dsDNA from irradiated cancer cells to DCs. Cancer Immunol. Res. 6 (2018), 910–920.
Michalski, S., de Oliveira Mann, C.C., Stafford, C.A., Witte, G., Bartho, J., Lammens, K., Hornung, V., Hopfner, K.-P., Structural basis for sequestration and autoinhibition of cGAS by chromatin. Nature 587 (2020), 678–682.
Zierhut, C., Yamaguchi, N., Paredes, M., Luo, J.-D., Carroll, T., Funabiki, H., The cytoplasmic DNA sensor cGAS promotes mitotic cell death. Cell 178 (2019), 302–315.e23.
Li, T., Huang, T., Du, M., Chen, X., Du, F., Ren, J., Chen, Z.J., Phosphorylation and chromatin tethering prevent cGAS activation during mitosis. Science, 371, 2021, eabc5386.
Buck, J., Grossen, P., Cullis, P.R., Huwyler, J., Witzigmann, D., Lipid-based DNA therapeutics: hallmarks of non-viral gene delivery. ACS Nano 13 (2019), 3754–3782.
Hajj, K.A., Whitehead, K.A., Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater., 2, 2017, 17056.
Liu, M.A., A comparison of plasmid DNA and mRNA as vaccine technologies. Vaccines, 7, 2019, 37.
Hu, Z., Chen, H., Long, Y., Li, P., Gu, Y., The main sources of circulating cell-free DNA: apoptosis, necrosis and active secretion. Crit. Rev. Oncol. Hematol., 157, 2021, 103166.
Rogers, J.C., Boldt, D., Kornfeld, S., Skinner, A., Valeri, C.R., Excretion of deoxyribonucleic acid by lymphocytes stimulated with phytohemagglutinin or antigen. Proc. Natl. Acad. Sci. USA 69 (1972), 1685–1689.
Perez-Riverol, Y., Bandla, C., Kundu, D.J., Kamatchinathan, S., Bai, J., Hewapathirana, S., John, N.S., Prakash, A., Walzer, M., Wang, S., Vizcaíno, J.A., The PRIDE database at 20 years: 2025 update. Nucleic Acids Res. 53 (2025), D543–D553.
Ying, W., Cheruku, P.S., Bazer, F.W., Safe, S.H., Zhou, B., Investigation of macrophage polarization using bone marrow derived macrophages. JoVE J., 76, 2013, 50323.e50323.
Endo, S., Sakamoto, Y., Kobayashi, E., Nakamura, A., Takai, T., Regulation of cytotoxic T lymphocyte triggering by PIR-B on dendritic cells. Proc. Natl. Acad. Sci. USA 105 (2008), 14515–14520.
Ueda, J., Saito, H., Watanabe, H., Evers, B.M., Novel and quantitative DNA dot-blotting method for assessment of in vivo proliferation. Am. J. Physiol. Gastrointest. Liver Physiol. 288 (2005), G842–G847.
Livak, K.J., Schmittgen, T.D., Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. methods 25 (2001), 402–408.
Anand, L., Rodriguez Lopez, C.M., ChromoMap: an R package for interactive visualization of multi-omics data and annotation of chromosomes. BMC Bioinf., 23, 2022, 33.
McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., Altshuler, D., Gabriel, S., Daly, M., DePristo, M.A., The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20 (2010), 1297–1303.
DePristo, M.A., Banks, E., Poplin, R., Garimella, K.V., Maguire, J.R., Hartl, C., Philippakis, A.A., Del Angel, G., Rivas, M.A., Hanna, M., et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43 (2011), 491–498.
Graw, S., Tang, J., Zafar, M.K., Byrd, A.K., Bolden, C., Peterson, E.C., Byrum, S.D., proteiNorm–A user-friendly tool for normalization and analysis of TMT and label-free protein quantification. ACS Omega 5 (2020), 25625–25633.
Aguilan, J.T., Kulej, K., Sidoli, S., Guide for protein fold change and p-value calculation for non-experts in proteomics. Mol. Omics 16 (2020), 573–582.
Babicki, S., Arndt, D., Marcu, A., Liang, Y., Grant, J.R., Maciejewski, A., Wishart, D.S., Heatmapper: web-enabled heat mapping for all. Nucleic Acids Res. 44 (2016), W147–W153.
