Conformal Radiotherapy Efficacy Depends on Monocyte IFN-I Signaling

Preclinical studies suggest radiotherapy (RT) promotes intratumoral monocyte infiltration by which these monocytes then acquire immunosuppressive properties and limit the efficacy of RT. However, the shield RT (SRT) performed in these preclinical studies differs from the conformal RT (CRT) currently used in the clinic, as CRT aims for minimal toxicity and personalized treatment by directing radiation only to the tumor through use of computerized tomography. To better understand the role of monocytes in regulating treatment efficacy, Tadepalli, Clements, and colleagues investigated the acute immune response to CRT in various tumor-bearing mouse models and showed that CRT more effectively induced tumor regression and extended survival compared to preclinical SRT whether given in a single ablative dose or multiple hypofractionated doses. Significantly higher proportions of intratumoral CD8⁺ T cells and activated monocytes were observed following CRT, along with fewer exhausted T cells and immunosuppressive tumor-associated macrophages (TAM). Moreover, transcriptomic and proteomic analyses revealed higher expression of IFN-I, IFN-stimulated genes, and cytokines/chemokines that promote T-cell recruitment and effector function in the activated monocytes following CRT. Depletion of monocytes, but not other myeloid cells, decreased the CD8⁺ T-cell response and CRT efficacy, suggesting that monocytes are recruited into tumors following CRT and promote T-cell function and tumor regression. Additionally, while knockout of the IFN-I receptor abolished the effect of CRT, inactivation of STING, a protein that stimulates IFN-I secretion, did not, suggesting CRT induces an IFN-dependent, STING-independent immune response. Furthermore, monocytes were found to be the main cells producing and responding to IFN-I in the tumor microenvironment, and adoptive transfer of wild-type monocytes into CRT-treated mice caused accumulation of activated monocytes, whereas transfer of monocytes lacking the IFN-I receptor caused their accumulation as TAMs, indicating that IFN-I signaling dictates monocyte fate. Finally, SRT was found to damage more healthy tissue than CRT, redirecting monocytes away from the tumor and into noncancerous tissue, possibly leading to the impaired immune response. Together, this study demonstrates that IFN-I sensing by monocytes enables an effective antitumor immune response following clinically relevant forms of RT.

Tadepalli S, Clements DR, Saravanan S, Arroyo Hornero R, Lüdtke A, Blackmore B, et al. Rapid recruitment and IFN-I–mediated activation of monocytes dictate focal radiotherapy efficacy. Sci Immunol 2023;8:eadd7446.

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