%0 Journal Article
%T 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
%A Abhishek Jha
%A David Ta£żeb
%A Gang Niu
%A Garima Gupta
%A Hans Kumar Ghayee
%A Ivana Jochmanova
%A Jan Zenka
%A Karel Pacak
%A Liping Li
%A Luma Abunimer
%A Markku Miettinen
%A Ondrej Uher
%A Thanh-Truc Huynh
%A Veronika Caisova
%A Xiaoyuan Chen
%A Ying Pang
%A Zhengping Zhuang
%J Archive of "Cancers".
%D 2019
%R 10.3390/cancers11050654
%X Therapeutic options for metastatic pheochromocytoma/paraganglioma (PHEO/PGL) are limited. Here, we tested an immunotherapeutic approach based on intratumoral injections of mannan-BAM with toll-like receptor ligands into subcutaneous PHEO in a mouse model. This therapy elicited a strong innate immunity-mediated antitumor response and resulted in a significantly lower PHEO volume compared to the phosphate buffered saline (PBS)-treated group and in a significant improvement in mice survival. The cytotoxic effect of neutrophils, as innate immune cells predominantly infiltrating treated tumors, was verified in vitro. Moreover, the combination of mannan-BAM and toll-like receptor ligands with agonistic anti-CD40 was associated with increased mice survival. Subsequent tumor re-challenge also supported adaptive immunity activation, reflected primarily by long-term tumor-specific memory. These results were further verified in metastatic PHEO, where the intratumoral injections of mannan-BAM, toll-like receptor ligands, and anti-CD40 into subcutaneous tumors resulted in significantly less intense bioluminescence signals of liver metastatic lesions induced by tail vein injection compared to the PBS-treated group. Subsequent experiments focusing on the depletion of T cell subpopulations confirmed the crucial role of CD8+ T cells in inhibition of bioluminescence signal intensity of liver metastatic lesions. These data call for a new therapeutic approach in patients with metastatic PHEO/PGL using immunotherapy that initially activates innate immunity followed by an adaptive immune response
%K pheochromocytoma
%K paraganglioma
%K metastatic
%K immunotherapy
%K innate immunity
%K adaptive immunity
%K toll-like receptor
%K pathogen-associated molecular patterns
%K neutrophil
%K T cell
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562455/