Dimethylaminomicheliolide Sensitizes Cancer Cells to Radiotherapy for Synergistic Combination with Immune Checkpoint Blockade

Abstract

Radiotherapy (RT) has demonstrated synergy with immune checkpoint blockade (ICB) in preclinical models. However, its potential as an immunoadjuvant is limited by low immunogenicity at low radiation doses and immunosuppression at high radiation doses. It is hypothesized that radiosensitizers can enhance both the anticancer and immunogenic effects of low-dose radiation. Herein the authors report the antitumor immunity of combined RT and immunotherapy with dimethylaminomicheliolide (DMAMCL), a prodrug of the anti-inflammatory sesquiterpene lactone micheliolide (MCL). DMAMCL sensitized cancer cells to a single fraction of RT in vitro by inducing apoptosis and DNA double-strand breaks. DMAMCL with 5 fractions of 2 Gy focal X-ray irradiation led to significant anticancer efficacy in subcutaneous and spontaneous models of murine cancer. DMAMCL-sensitized RT upregulated programmed death-ligand 1 (PD-L1) expression in the tumors. Combination of DMAMCL-sensitized RT with anti-PD-L1 ICB significantly enhanced antitumor efficacy by increasing tumor-infiltrating CD4 + and CD8 + T cells and establishing immune memory.

Pharmacological potential of micheliolide: A focus on anti-inflammatory and anticancer activities

“…DMAMCL sensitized cancer cells to a single fraction of radiotherapy in vitro by inducing apoptosis and DNA double-strand breaks. The combination of DMAMCL-sensitized radiotherapy with anti-PD-L1 ICB significantly enhanced antitumor efficacy by increasing tumor-infiltrating CD4 + and CD8 + T cells and establishing immune memory [ 18 ].…”

“…MCL is a potentially stable sesquiterpene lactone [ 18 ], which can be isolated from Magnolia grandiflora L ., Michelia champaca L ., and Michelia compressa (Maxim.) Sarg .…”

“…Sarg . MCL and its Michael adduct dimethylaminomicheliolide (DMAMCL) display significant cytotoxicity against tumors [ [18] , [19] , [20] , [21] , [22] , [23] , [24] ]. MCL is known to be firstly isolated by Ogura, Cordell [ 25 ] from Michelia compressa (Maxim.)…”