“One-two punch” vs. “double-edged sword” scenarios for tumor radiosensitization strategies exploiting IRAK1 inhibitors. (A) Simplified view of RT-induced antitumor immunity. DAMPs and cytokines (i.e., IL-1β) released by irradiated tumor cells are recognized by cell surface IL-1R/TLRs on surrounding stromal DCs and macrophages, stimulating their activation, maturation, and antigen presentation activity toward T-cells in lymph nodes, and ultimately unleashing tumor-specific T-cells against the irradiated tumor (as well as distant tumors not pictured here). TAA, tumor-associated antigen; DAMPs, damage-associated molecular patterns; IT, immunotherapy; TLRa, toll-like receptor agonist; DC, dendritic cell; ag pres., antigen presentation. *IT (with TLRa) is optional and acts as a boost for the immune events otherwise described in the figure. (B) Simplified views of the IRAK1-mediated response to RT (left; tumor cell-intrinsic antiapoptotic response) and DAMP-bound TLRs (right, innate immune response). Note that while IRAK1 catalytic activity is required for the tumor response to RT (illustrated by green glare), it is largely dispensable for immune IRAK1 signaling. (C) “One-two punch” scenario, as afforded by a highly specific IRAK1 inhibitor with no activity against IRAK4. Such drugs would be expected to both blunt intrinsic tumor radioresistance (which depends on IRAK1 kinase activity) and spare IRAK1 mediated-antitumor immunity (which is less reliant on IRAK1 catalytic activity), resulting in a “one-two punch” on the tumor. The double-punch is illustrated by two red dart target symbols on the tumor. (D) “Double-edged sword” scenario, as afforded by a less specific IRAK1i with similar activity against IRAK4. Such IRAK1/4i would be expected to block both the tumor and immune responses to RT (each of which depends on IRAK4 catalytic activity; see text). Thus, in this scenario, intrinsic tumor radiosensitization activity would be retained but at the expense of blunting the immune component. A small, residual “punch” from the immune system on the tumor is indicated to further emphasize the detrimental effects of IRAK1/4i relative to the “one-two punch” effects of specific IRAK1i [compare with (C)]. Figure design by Ni-Ka Ford, printed with permission from with permission from ©Mount Sinai Health System.
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