Immunotherapy represents a revolutionary advancement in cancer treatment, which has traditionally focused on T cells; however, the role of B cells in cancer immunotherapy has gained interest because of their role in antigen presentation, antibody production, and cytokine release. In this study, we examined the role of B cells in previously developed intratumoral MBTA therapy (mannan-BAM, TLR ligands, and anti-CD40 antibody) in murine models of MTT pheochromocytoma. The results indicated that B cells significantly enhance the success of MBTA therapy, with wild-type mice exhibiting a lower tumor incidence and smaller tumors compared with B cell-deficient mice. Increased IL-6 and TNF-alpha levels indicated severe inflammation and a potential cytokine storm in B cell-deficient mice. Neutralization of TNF-alpha ameliorated these complications but resulted in increased tumor recurrence. The results highlight the important role of B cells in enhancing the immune response and maintaining immune homeostasis during MBTA therapy. Our findings offer new insights into improving therapeutic outcomes.

Department of Medical Biology Faculty of Science University of South Bohemia Ceske Budejovice 37005 Czech Republic

Department of Pathological Physiology Faculty of Medicine Masaryk University Brno 62500 Czech Republic; Department of Physiology Faculty of Medicine Masaryk University Brno 62500 Czech Republic; BIOCEV 1st Faculty of Medicine Charles University Vestec 25250 Czech Republic

Neuro Oncology Branch National Cancer Institute NIH Bethesda 20892 MD USA

Research Animal Management Branch Eunice Kennedy Shriver National Institute of Child Health and Human Development NIH Bethesda 20892 MD USA

Section on Medical Neuroendocrinology Eunice Kennedy Shriver National Institute of Child Health and Human Development NIH Bethesda 20892 MD USA

Section on Medical Neuroendocrinology Eunice Kennedy Shriver National Institute of Child Health and Human Development NIH Bethesda 20892 MD USA; Department of Pathological Physiology Faculty of Medicine Masaryk University Brno 62500 Czech Republic

Zobrazit více v PubMed

Uher O, Hadrava Vanova K, Taieb D, Calsina B, Robledo M, Clifton-Bligh R, et al. The Immune Landscape of Pheochromocytoma and Paraganglioma: Current Advances and Perspectives. Endocr Rev. 2024. PubMed PMC

Uher O, Caisova V, Hansen P, Kopecky J, Chmelar J, Zhuang Z, et al. Coley’s immunotherapy revived: Innate immunity as a link in priming cancer cells for an attack by adaptive immunity. Semin Oncol. 2019. PubMed PMC

Caisova V, Li L, Gupta G, Jochmanova I, Jha A, Uher O, et al. The Significant Reduction or Complete Eradication of Subcutaneous and Metastatic Lesions in a Pheochromocytoma Mouse Model after Immunotherapy Using Mannan-BAM, TLR Ligands, and Anti-CD40. Cancers (Basel). 2019;11(5). PubMed PMC

Caisova V, Uher O, Nedbalova P, Jochmanova I, Kvardova K, Masakova K, et al. Effective cancer immunotherapy based on combination of TLR agonists with stimulation of phagocytosis. Int Immunopharmacol. 2018;59:86–96. PubMed

Medina R, Wang H, Caisova V, Cui J, Indig IH, Uher O, et al. Induction of Immune Response Against Metastatic Tumors via Vaccination of Mannan-BAM, TLR Ligands and Anti-CD40 Antibody (MBTA). Adv Ther (Weinh). 2020;3(9). PubMed PMC

Uher O, Hadrava Vanova K, Lencova R, Frejlachova A, Wang H, Zhuang Z, et al. Intratumoral immunotherapy of murine pheochromocytoma shows no age-dependent differences in its efficacy. Front Endocrinol (Lausanne). 2023;14:1030412. PubMed PMC

Uher O, Huynh TT, Zhu B, Horn LA, Caisova V, Hadrava Vanova K, et al. Identification of Immune Cell Infiltration in Murine Pheochromocytoma during Combined Mannan-BAM, TLR Ligand, and Anti-CD40 Antibody-Based Immunotherapy. Cancers (Basel). 2021;13(16). PubMed PMC

Waldmannova E, Caisova V, Faberova J, Svackova P, Kovarova M, Svackova D, et al. The use of Zymosan A and bacteria anchored to tumor cells for effective cancer immunotherapy: B16-F10 murine melanoma model. Int Immunopharmacol. 2016;39:295–306. PubMed

Calsina B, Pineiro-Yanez E, Martinez-Montes AM, Caleiras E, Fernandez-Sanroman A, Monteagudo M, et al. Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma. Nat Commun. 2023;14(1):1122. PubMed PMC

Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang TH, et al. The Immune Landscape of Cancer. Immunity. 2018;48(4):812–30 e14. PubMed PMC

Zethoven M, Martelotto L, Pattison A, Bowen B, Balachander S, Flynn A, et al. Single-nuclei and bulk-tissue gene-expression analysis of pheochromocytoma and paraganglioma links disease subtypes with tumor microenvironment. Nat Commun. 2022;13(1):6262. PubMed PMC

Ghosal S, Vanova KH, Uher O, Das S, Patel M, Meuter L, et al. Immune signature of pheochromocytoma and paraganglioma in context of neuroendocrine neoplasms associated with prognosis. Endocrine. 2023;79(1):171–9. PubMed PMC

Medina R, Wang HR, Caisova V, Cui J, Indig IH, Uher O, et al. Induction of Immune Response against Metastatic Tumors via Vaccination of Mannan-BAM, TLR Ligands, and Anti-CD40 Antibody (MBTA). Adv Ther-Germany. 2020. PubMed PMC

Sagiv-Barfi I, Czerwinski DK, Shree T, Lohmeyer JJK, Levy R. Intratumoral immunotherapy relies on B and T cell collaboration. Sci Immunol. 2022;7(71):eabn5859. PubMed PMC

Damsky W, Jilaveanu L, Turner N, Perry C, Zito C, Tomayko M, et al. B cell depletion or absence does not impede anti-tumor activity of PD-1 inhibitors. J Immunother Cancer. 2019;7(1):153. PubMed PMC

Rawat K, Tewari A, Morrisson MJ, Wager TD, Jakubzick CV. Redefining innate natural antibodies as important contributors to anti-tumor immunity. Elife. 2021;10. PubMed PMC

Rogers D, Vila-Leahey A, Pessoa AC, Oldford S, Marignani PA, Marshall JS. Ranitidine Inhibition of Breast Tumor Growth Is B Cell Dependent and Associated With an Enhanced Antitumor Antibody Response. Front Immunol. 2018;9:1894. PubMed PMC

Shah S, Divekar AA, Hilchey SP, Cho HM, Newman CL, Shin SU, et al. Increased rejection of primary tumors in mice lacking B cells: inhibition of anti-tumor CTL and TH1 cytokine responses by B cells. Int J Cancer. 2005;117(4):574–86. PubMed

Gorosito Serran M, Tosello Boari J, Fiocca Vernengo F, Beccaria CG, Ramello MC, Bermejo DA, et al. Unconventional Pro-inflammatory CD4(+) T Cell Response in B Cell-Deficient Mice Infected with Trypanosoma cruzi. Front Immunol. 2017;8:1548. PubMed PMC