Abstract
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.
Highlights
Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare catecholamine-producing neuroendocrine/neural crest cell tumors arising from the adrenal medulla and extra-adrenal paraganglia, respectively [1]
We showed that the application of mannan anchored to a tumor cell membrane via BAM along with TLR ligands (R-848, poly(I:C), lipoteichoic acid (LTA))
Similar to B6(Cg)-Tyrc-2J /J mice, in B6.CB17-Prkdcscid /SzJ mice, the subcutaneous PHEO volume remained stable in the mannan-BAM and TLR ligands (MBT)-treated group compared to the phosphate buffered saline (PBS)-treated group
Summary
Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare catecholamine-producing neuroendocrine/neural crest cell tumors arising from the adrenal medulla and extra-adrenal paraganglia, respectively [1]. Immunotherapy, in which immune cells of a patient are used to attack and subsequently eliminate tumor cells, is currently one of the most extensively studied therapeutic approaches in cancer research [3,4]. Only one experimental study proposed the use of immunotherapy in PHEO/PGL, chromogranin A, as a potential treatment target [8]. Immunization with chromogranin A peptides induced the production of cytotoxic T cells with subsequent elimination of chromogranin A expressing PHEO cells. Chromogranin A peptides were suggested as a potential anti-tumor vaccine in PHEO patients with risk of metastatic disease [8]. Two clinical trials focusing on the application of checkpoint inhibitors ( nivolumab, ipilimumab, and pembrolizumab) in rare tumors, including PHEO/PGL, were initiated and are in the stage of patient recruitment (ClinicalTrials.gov Identifier: NCT02834013 and NCT02721732)
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