References
-
Abramson, J. S. et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet 396, 839–852 (2020).
-
Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017).
-
Schuster, S. J. et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N. Engl. J. Med. 377, 2545–2554 (2017).
-
Mullard, A. FDA approves first CAR T therapy. Nat. Rev. Drug Discov. 16, 669 (2017).
-
Wang, M. et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N. Engl. J. Med. 382, 1331–1342 (2020).
-
Xia, L. et al. Targeting triple-negative breast cancer with combination therapy of EGFR CAR T cells and CDK7 inhibition. Cancer Immunol. Res. 9, 707–722 (2021).
-
Stüber, T. et al. Inhibition of TGF-β-receptor signaling augments the antitumor function of ROR1-specific CAR T-cells against triple-negative breast cancer. J. Immunother. Cancer 8, e000676 (2020).
-
Erler, P. et al. Multi-armored allogeneic MUC1 CAR T cells enhance efficacy and safety in triple-negative breast cancer. Sci. Adv. 10, eadn9857 (2024).
-
Raj, D. et al. Switchable CAR-T cells mediate remission in metastatic pancreatic ductal adenocarcinoma. Gut 68, 1052–1064 (2019).
-
Li, N. et al. The IgG4 hinge with CD28 transmembrane domain improves VHH-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer. Nat. Commun. 14, 1986 (2023).
-
Yuan, Y. et al. Cell surface GRP78-directed CAR-T cells are effective at treating human pancreatic cancer in preclinical models. Transl. Oncol. 39, 101803 (2024).
-
Ghasempour, S. & Freeman, S. A. The glycocalyx and immune evasion in cancer. FEBS J. https://doi.org/10.1111/febs.16236 (2021).
-
Öhlund, D., Elyada, E. & Tuveson, D. Fibroblast heterogeneity in the cancer wound. J. Exp. Med. 211, 1503–1523 (2014).
-
Connor, A. A. & Gallinger, S. Pancreatic cancer evolution and heterogeneity: integrating omics and clinical data. Nat. Rev. Cancer 22, 131–142 (2022).
-
Kankeu Fonkoua, L. A., Sirpilla, O., Sakemura, R., Siegler, E. L. & Kenderian, S. S. CAR T cell therapy and the tumor microenvironment: current challenges and opportunities. Mol. Ther. 25, 69–77 (2022).
-
Beatson, R. et al. The mucin MUC1 modulates the tumor immunological microenvironment through engagement of the lectin Siglec-9. Nat. Immunol. 17, 1273–1281 (2016).
-
Park, S. et al. Immunoengineering can overcome the glycocalyx armour of cancer cells. Nat. Mater. 23, 429–438 (2024).
-
Gubbels, J. A. A. et al. MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells. Mol. Cancer 9, 11 (2010).
-
Pedram, K. et al. Design of a mucin-selective protease for targeted degradation of cancer-associated mucins. Nat. Biotechnol. https://doi.org/10.1038/s41587-023-01840-6 (2023).
-
Park, S. et al. Leucine zipper-based SAIM imaging identifies therapeutic agents to disrupt the cancer cell glycocalyx for enhanced immunotherapy. Preprint at https://doi.org/10.1101/2024.12.05.627089 (2024).
-
Park, S. et al. Collagen mineralization decreases NK cell-mediated cytotoxicity of breast cancer cells via increased glycocalyx thickness. Adv. Mater. 2311505 https://doi.org/10.1002/adma.202311505 (2024).
-
Hollander, E. E. et al. N-glycosylation by Mgat5 imposes a targetable constraint on immune-mediated tumor clearance. JCI Insight 9, e178804 (2024).
-
Posey, A. D. et al. Engineered CAR T cells targeting the cancer-associated Tn-glycoform of the membrane mucin MUC1 control adenocarcinoma. Immunity 44, 1444–1454 (2016).
-
Supimon, K. et al. Anti-mucin 1 chimeric antigen receptor T cells for adoptive T cell therapy of cholangiocarcinoma. Sci. Rep. 11, 6276 (2021).
-
Mei, Z. et al. MUC1 as a target for CAR-T therapy in head and neck squamous cell carinoma. Cancer Med. 9, 640–652 (2020).
-
Zhou, R. et al. CAR T cells targeting the tumor MUC1 glycoprotein reduce triple-negative breast cancer growth. Front. Immunol. 10, 1149 (2019).
-
Yazdanifar, M. et al. Overcoming immunological resistance enhances the efficacy of a novel anti-tMUC1-CAR T cell treatment against pancreatic ductal adenocarcinoma. Cells 8, 1070 (2019).
-
Wilkie, S. et al. Retargeting of human T cells to tumor-associated MUC1: the evolution of a chimeric antigen receptor. J. Immunol. 180, 4901–4909 (2008).
-
Van Elssen, C. H. M. J. et al. Expression of aberrantly glycosylated Mucin-1 in ovarian cancer. Histopathology 57, 597–606 (2010).
-
Cloosen, S. et al. Cancer specific Mucin-1 glycoforms are expressed on multiple myeloma. Br. J. Haematol. 135, 513–516 (2006).
-
Andrulis, M. et al. Expression of Mucin-1 in multiple myeloma and its precursors: correlation with glycosylation and subcellular localization. Histopathology 64, 799–806 (2014).
-
Gutierrez, R. et al. Phase I experience with first in class TnMUC1 targeted chimeric antigen receptor T-cells in patients with advanced TnMUC1 positive solid tumors. JCO 39, e14513–e14513 (2021).
-
Greco, B. et al. Disrupting N-glycan expression on tumor cells boosts chimeric antigen receptor T cell efficacy against solid malignancies. Sci. Transl. Med. 14, eabg3072 (2022).
-
Zhou, J. Y. & Cobb, B. A. Glycans in immunologic health and disease. Annu. Rev. Immunol. 39, 511–536 (2021).
-
Costa, C. et al. Abnormal protein glycosylation and activated PI3K/Akt/mTOR pathway: role in bladder cancer prognosis and targeted therapeutics. PLoS ONE 10, e0141253 (2015).
-
Davidson, B. et al. Carbohydrate antigen expression in primary tumors, metastatic lesions, and serous effusions from patients diagnosed with epithelial ovarian carcinoma: evidence of up-regulated Tn and Sialyl Tn antigen expression in effusions. Hum. Pathol. 31, 1081–1087 (2000).
-
Springer, G. F., Desai, P. R. & Banatwala, I. Blood group MN antigens and precursors in normal and malignant human breast glandular tissue. J. Natl. Cancer Inst. 54, 335–339 (1975).
-
Zhang, S. et al. Expression of potential target antigens for immunotherapy on primary and metastatic prostate cancers. Clin. Cancer Res. 4, 295–302 (1998).
-
Remmers, N. et al. Aberrant expression of mucin core proteins and o-linked glycans associated with progression of pancreatic cancer. Clin. Cancer Res. 19, 1981–1993 (2013).
-
Ohshio, G. et al. Distribution of Tn antigen recognized by an anti-Tn monoclonal antibody (MLS128) in normal and malignant tissues of the digestive tract. J. Cancer Res. Clin. Oncol. 121, 247–252 (1995).
-
López-Ferrer, A., Barranco, C. & de Bolós, C. Differences in the O-glycosylation patterns between lung squamous cell carcinoma and adenocarcinoma. Am. J. Clin. Pathol. 118, 749–755 (2002).
-
Sun, X., Ju, T. & Cummings, R. D. Differential expression of Cosmc, T-synthase and mucins in Tn-positive colorectal cancers. BMC Cancer 18, 827 (2018).
-
Ju, T. & Cummings, R. D. A unique molecular chaperone Cosmc required for activity of the mammalian core 1 beta 3-galactosyltransferase. Proc. Natl. Acad. Sci. USA 99, 16613–16618 (2002).
-
Ju, T. et al. Human tumor antigens Tn and sialyl Tn arise from mutations in Cosmc. Cancer Res. 68, 1636–1646 (2008).
-
Schietinger, A. et al. A mutant chaperone converts a wild-type protein into a tumor-specific antigen. Science 314, 304–308 (2006).
-
Ju, T. & Cummings, R. D. Protein glycosylation: chaperone mutation in Tn syndrome. Nature 437, 1252 (2005).
-
Nogimori, K. et al. Increased expression levels of ppGalNAc-T13 in lung cancers: Significance in the prognostic diagnosis. Int. J. Oncol. 49, 1369–1376 (2016).
-
Huang, M.-J. et al. Knockdown of GALNT1 suppresses malignant phenotype of hepatocellular carcinoma by suppressing EGFR signaling. Oncotarget 6, 5650–5665 (2015).
-
Park, J.-H. et al. Critical roles of mucin 1 glycosylation by transactivated polypeptide N-acetylgalactosaminyltransferase 6 in mammary carcinogenesis. Cancer Res. 70, 2759–2769 (2010).
-
Wang, Z.-Q. et al. Role of the polypeptide N-acetylgalactosaminyltransferase 3 in ovarian cancer progression: possible implications in abnormal mucin O-glycosylation. Oncotarget 5, 544–560 (2014).
-
Taniuchi, K. et al. Overexpression of GalNAc-transferase GalNAc-T3 promotes pancreatic cancer cell growth. Oncogene 30, 4843–4854 (2011).
-
Ju, T., Aryal, R. P., Kudelka, M. R., Wang, Y. & Cummings, R. D. The Cosmc connection to the Tn antigen in cancer. Cancer Biomark. 14, 63–81 (2014).
-
Babino, A. et al. Tn antigen is a pre-cancerous biomarker in breast tissue and serum in n-nitrosomethylurea-induced rat mammary carcinogenesis. Int. J. Cancer 86, 753–759 (2000).
-
O’Connor, J. C., Julian, J., Lim, S. D. & Carson, D. D. MUC1 expression in human prostate cancer cell lines and primary tumors. Prostate Cancer Prostatic Dis. 8, 36–44 (2005).
-
Walsh, M. D., Luckie, S. M., Cummings, M. C., Antalis, T. M. & McGuckin, M. A. Heterogeneity of MUC1 expression by human breast carcinoma cell lines in vivo and in vitro. Breast Cancer Res. Treat. 58, 255–266 (1999).
-
Hirabayashi, K. et al. Dual targeting CAR-T cells with optimal costimulation and metabolic fitness enhance antitumor activity and prevent escape in solid tumors. Nat. Cancer 2, 904–918 (2021).
-
Haubner, S. et al. Cooperative CAR targeting to selectively eliminate AML and minimize escape. Cancer Cell 41, 1871–1891.e6 (2023).
-
Katsarou, A. et al. Combining a CAR and a chimeric costimulatory receptor enhances T cell sensitivity to low antigen density and promotes persistence. Sci. Transl. Med. 13, eabh1962 (2021).
-
Hassan, R. et al. Tumor-directed radiation and the immunotoxin SS1P in the treatment of mesothelin-expressing tumor xenografts. Clin. Cancer Res. 12, 4983–4988 (2006).
-
Mack, M., Riethmüller, G. & Kufer, P. A small bispecific antibody construct expressed as a functional single-chain molecule with high tumor cell cytotoxicity. Proc. Natl. Acad. Sci. USA 92, 7021–7025 (1995).
-
Boucher, J. C. et al. CD28 costimulatory domain-targeted mutations enhance chimeric antigen receptor T-cell function. Cancer Immunol. Res. 9, 62–74 (2021).
-
Li, C.-L. et al. Repurposed itraconazole for use in the treatment of malignancies as a promising therapeutic strategy. Biomed. Pharmacother. 154, 113616 (2022).
-
Van Cauteren, H., Heykants, J., De Coster, R. & Cauwenbergh, G. Itraconazole: pharmacologic studies in animals and humans. Rev. Infect. Dis. 9, S43–S46 (1987).
-
Lestner, J. M. et al. Toxicodynamics of itraconazole: implications for therapeutic drug monitoring. Clin. Infect. Dis. 49, 928–930 (2009).
-
Shim, J. S. et al. Divergence of antiangiogenic activity and hepatotoxicity of different stereoisomers of itraconazole. Clin. Cancer Res. 22, 2709–2720 (2016).
-
Wörn, A. & Plückthun, A. Stability engineering of antibody single-chain Fv fragments. J. Mol. Biol. 305, 989–1010 (2001).
-
Röthlisberger, D., Honegger, A. & Plückthun, A. Domain interactions in the Fab fragment: a comparative evaluation of the single-chain Fv and Fab format engineered with variable domains of different stability. J. Mol. Biol. 347, 773–789 (2005).
-
Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).
-
Sommermeyer, D. et al. Fully human CD19-specific chimeric antigen receptors for T-cell therapy. Leukemia 31, 2191–2199 (2017).
-
Ghorashian, S. et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat. Med. 25, 1408–1414 (2019).
-
Lavrsen, K. et al. Aberrantly glycosylated MUC1 is expressed on the surface of breast cancer cells and a target for antibody-dependent cell-mediated cytotoxicity. Glycoconj. J. 30, 227–236 (2013).
-
Macías-León, J. et al. Structural characterization of an unprecedented lectin-like antitumoral anti-MUC1 antibody. Chem. Commun. 56, 15137–15140 (2020).
-
Wang, S., You, L., Dai, M. & Zhao, Y. Mucins in pancreatic cancer: a well-established but promising family for diagnosis, prognosis and therapy. J. Cell Mol. Med. 24, 10279–10289 (2020).
-
Sanchez, J.-F. et al. Biochemical and structural analysis of Helix pomatia agglutinin. A hexameric lectin with a novel fold. J. Biol. Chem. 281, 20171–20180 (2006).
-
Radhakrishnan, P. et al. Immature truncated O-glycophenotype of cancer directly induces oncogenic features. Proc. Natl. Acad. Sci. USA 111, E4066–E4075 (2014).
-
Itzkowitz, S. et al. Expression of Tn, sialosyl Tn, and T antigens in human pancreas. Gastroenterology 100, 1691–1700 (1991).
-
Barr, N., Taylor, C. R., Young, T. & Springer, G. F. Are pancarcinoma T and Tn differentiation antigens? Cancer 64, 834–841 (1989).
-
Bulteau, F. et al. Targeting Tn-antigen-positive human tumors with a recombinant human macrophage galactose C-type lectin. Mol. Pharm. 19, 235–245 (2022).
-
Lenza, M. P. et al. Structural insights into Siglec-15 reveal glycosylation dependency for its interaction with T cells through integrin CD11b. Nat. Commun. 14, 3496 (2023).
-
Dobrin, A. et al. Synthetic dual co-stimulation increases the potency of HIT and TCR-targeted cell therapies. Nat. Cancer 5, 760–773 (2024).
-
McKenna, M. K. et al. Novel banana lectin CAR-T cells to target pancreatic tumors and tumor-associated stroma. J. Immunother. Cancer 11, e005891 (2023).
-
Del Bufalo, F. et al. GD2-CART01 for Relapsed or refractory high-risk neuroblastoma. N. Engl. J. Med. 388, 1284–1295 (2023).
-
Meléndez, A. V. et al. Novel lectin-based chimeric antigen receptors target Gb3-positive tumour cells. Cell Mol. Life Sci. 79, 513 (2022).
-
Malaker, S. A. et al. The mucin-selective protease StcE enables molecular and functional analysis of human cancer-associated mucins. Proc. Natl. Acad. Sci. USA 116, 7278–7287 (2019).
-
Hirao, T., Sakamoto, Y., Kamada, M., Hamada, S. & Aono, T. Tn antigen, a marker of potential for metastasis of uterine cervix cancer cells. Cancer 72, 154–159 (1993).
-
Terasawa, K., Furumoto, H., Kamada, M. & Aono, T. Expression of Tn and sialyl-Tn antigens in the neoplastic transformation of uterine cervical epithelial cells. Cancer Res. 56, 2229–2232 (1996).
-
Byrd, J. C. & Bresalier, R. S. Mucins and mucin binding proteins in colorectal cancer. Cancer Metastasis Rev. 23, 77–99 (2004).
-
Hagerty, B. et al. Novel humanized mesothelin-expressing genetically engineered mouse models underscore challenges in delivery of complex therapeutics to pancreatic cancers. Mol. Cancer Ther. 20, 2082–2092 (2021).
-
Zervos, E., Agle, S., Freistaedter, A. G., Jones, G. J. B. & Roper, R. L. Murine mesothelin: characterization, expression, and inhibition of tumor growth in a murine model of pancreatic cancer. J. Exp. Clin. Cancer Res. 35, 39 (2016).
