PMID- 38298111 OWN - NLM STAT- MEDLINE DCOM- 20240411 LR - 20240425 IS - 2198-3844 (Electronic) IS - 2198-3844 (Linking) VI - 11 IP - 14 DP - 2024 Apr TI - rWTC-MBTA Vaccine Induces Potent Adaptive Immune Responses Against Glioblastomas via Dynamic Activation of Dendritic Cells. PG - e2308280 LID - 10.1002/advs.202308280 [doi] LID - 2308280 AB - Despite strides in immunotherapy, glioblastoma multiforme (GBM) remains challenging due to low inherent immunogenicity and suppressive tumor microenvironment. Converting "cold" GBMs to "hot" is crucial for immune activation and improved outcomes. This study comprehensively characterized a therapeutic vaccination strategy for preclinical GBM models. The vaccine consists of Mannan-BAM-anchored irradiated whole tumor cells, Toll-like receptor ligands [lipoteichoic acid (LTA), polyinosinic-polycytidylic acid (Poly (I:C)), and resiquimod (R-848)], and anti-CD40 agonistic antibody (rWTC-MBTA). Intracranial GBM models (GL261, SB28 cells) are used to evaluate the vaccine efficacy. A substantial number of vaccinated mice exhibited complete regression of GBM tumors in a T-cell-dependent manner, with no significant toxicity. Long-term tumor-specific immune memory is confirmed upon tumor rechallenge. In the vaccine-draining lymph nodes of the SB28 model, rWTC-MBTA vaccination triggered a major rise in conventional dendritic cell type 1 (cDC1) 12 h post-treatment, followed by an increase in conventional dendritic cell type 2 (cDC2), monocyte-derived dendritic cell (moDC), and plasmacytoid dendritic cell (pDC) on Day 5 and Day 13. Enhanced cytotoxicity of CD4+ and CD8+ T cells in vaccinated mice is verified in co-culture with tumor cells. Analyses of immunosuppressive signals (T-cell exhaustion, myeloid-derived suppressor cells (MDSC), M2 macrophages) in the GBM microenvironment suggest potential combinations with other immunotherapies for enhanced efficacy. In conclusion, the authors findings demonstrate that rWTC-MBTA induces potent and long-term adaptive immune responses against GBM. CI - (c) 2024 The Authors. Advanced Science published by Wiley-VCH GmbH. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. FAU - Wang, Herui AU - Wang H AUID- ORCID: 0000-0003-2293-4819 AD - Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 10022, USA. FAU - Medina, Rogelio AU - Medina R AD - Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 10022, USA. FAU - Ye, Juan AU - Ye J AD - Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 10022, USA. FAU - Zhang, Yaping AU - Zhang Y AD - Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 10022, USA. FAU - Chakraborty, Samik AU - Chakraborty S AD - NE1 Inc., New York, NY, 10022, USA. FAU - Valenzuela, Alex AU - Valenzuela A AD - Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 10022, USA. FAU - Uher, Ondrej AU - Uher O AD - Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA. FAU - Hadrava Vanova, Katerina AU - Hadrava Vanova K AD - Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA. FAU - Sun, Mitchell AU - Sun M AD - Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 10022, USA. FAU - Sang, Xueyu AU - Sang X AD - Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 10022, USA. FAU - Park, Deric M AU - Park DM AD - John Theurer Cancer Center, HUMC, Hackensack Meridian School of Medicine, 92 2nd St, Hackensack, NJ, 07601, USA. FAU - Zenka, Jan AU - Zenka J AD - Department of Medical Biology, Faculty of Science, University of South Bohemia, Ceske Budejovice, 37005, Czech Republic. FAU - Gilbert, Mark R AU - Gilbert MR AD - Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 10022, USA. FAU - Pacak, Karel AU - Pacak K AD - Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA. FAU - Zhuang, Zhengping AU - Zhuang Z AUID- ORCID: 0000-0002-0009-7370 AD - Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 10022, USA. LA - eng GR - Intramural Research Programs of the National Institutes of Health (NIH), including the National Cancer Institute (NCI) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/ PT - Journal Article DEP - 20240131 PL - Germany TA - Adv Sci (Weinh) JT - Advanced science (Weinheim, Baden-Wurttemberg, Germany) JID - 101664569 RN - 0 (Vaccines) SB - IM MH - Mice MH - Animals MH - *Glioblastoma/metabolism MH - CD8-Positive T-Lymphocytes MH - *Vaccines/metabolism MH - Dendritic Cells MH - Immunity MH - Tumor Microenvironment PMC - PMC11005728 OTO - NOTNLM OT - dendritic cells OT - glioblastoma OT - immunotherapy OT - rWTC-MBTA vaccine OT - tumor microenvironment COIS- The authors declare no conflict of interest. EDAT- 2024/02/01 06:42 MHDA- 2024/04/11 06:42 PMCR- 2024/01/31 CRDT- 2024/02/01 03:18 PHST- 2023/12/19 00:00 [revised] PHST- 2023/10/31 00:00 [received] PHST- 2024/04/11 06:42 [medline] PHST- 2024/02/01 06:42 [pubmed] PHST- 2024/02/01 03:18 [entrez] PHST- 2024/01/31 00:00 [pmc-release] AID - ADVS7370 [pii] AID - 10.1002/advs.202308280 [doi] PST - ppublish SO - Adv Sci (Weinh). 2024 Apr;11(14):e2308280. doi: 10.1002/advs.202308280. Epub 2024 Jan 31.