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Review
. 2024 Jul 1;221(7):e20232101.
doi: 10.1084/jem.20232101. Epub 2024 May 21.

Radiotherapy and immunology

Liangliang Wang #  1   2 , Connor Lynch #  1   2 , Sean P Pitroda #  1   2 , András Piffkó  1   2   3 , Kaiting Yang  1   2 , Amy K Huser  1 , Hua Laura Liang  1   2 , Ralph R Weichselbaum  1   2
Affiliations
Review

Radiotherapy and immunology

Liangliang Wang et al. J Exp Med. .

Abstract

The majority of cancer patients receive radiotherapy during the course of treatment, delivered with curative intent for local tumor control or as part of a multimodality regimen aimed at eliminating distant metastasis. A major focus of research has been DNA damage; however, in the past two decades, emphasis has shifted to the important role the immune system plays in radiotherapy-induced anti-tumor effects. Radiotherapy reprograms the tumor microenvironment, triggering DNA and RNA sensing cascades that activate innate immunity and ultimately enhance adaptive immunity. In opposition, radiotherapy also induces suppression of anti-tumor immunity, including recruitment of regulatory T cells, myeloid-derived suppressor cells, and suppressive macrophages. The balance of pro- and anti-tumor immunity is regulated in part by radiotherapy-induced chemokines and cytokines. Microbiota can also influence radiotherapy outcomes and is under clinical investigation. Blockade of the PD-1/PD-L1 axis and CTLA-4 has been extensively investigated in combination with radiotherapy; we include a review of clinical trials involving inhibition of these immune checkpoints and radiotherapy.

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Conflict of interest statement

Disclosures: H.L. Liang reported grants from the National Institutes of Health outside the submitted work. R.R. Weichselbaum had stock and other ownership interests with Boost Therapeutics, Immvira LLC, Reflexion Pharmaceuticals, Coordination Pharmaceuticals Inc., Magi Therapeutics, Oncosenescence, Aqualung Therapeutics Corporation, Cyntegron, and PersonaDX. He has served in a consulting or advisory role for Aettis Inc., AstraZeneca, Coordination Pharmaceuticals, Genus, Merck Serono S.A., Nano Proteagen, NKGen Biotech, Shuttle Pharmaceuticals, Highlight Therapeutics, S.L., and Aqualung Therapeutics Corporation. He has research grants with Varian and Regeneron. He has a patent pending: “Methods and kits for diagnosis and triage of patients with colorectal liver metastases” (PCT/US2019/028071). He is a founder of Persona Dx and has stock. He has received compensation, including travel, accommodations, and expense reimbursement, from AstraZeneca, Boehringer Ingelheim, and Merck Serono SA. S.P. Pitroda has stock and ownership in PersonaDx. No other disclosures were reported.

Figures

Figure 1.
Figure 1.
IR reprograms the TME, initiating both pro-tumor and anti-tumor effects. Host immune status and other factors, such as microbiome populations, can affect tumor immunity. Left: Anti-tumor effects of IR. DCs are activated by RNA and DNA sensing pathways, which results in production of type I IFN, IFN-stimulated genes (ISGs), cytokines, and chemokines. DCs and inflammatory macrophage activate T cells to produce more IFN-γ, TNF-α, and granzyme B (GZMB), and kill tumor cells. Right: Pro-tumor effects of IR. IR induces PD-L1 and CTLA-4 expression in tumors. IR also induces infiltration of MDSCs, TAMs, and Tregs, which collectively inhibit T cell cytotoxic function and promote tumor growth. IR also induces overexpression of purinergic signaling to introduce radioresistance. Bottom: Outside of the tumor, products of certain bacteria strains activate or inhibit DC functions via TLRs. Fungus overgrowth or certain metabolites result in T cell exhaustion or radioresistance, respectively. MMP, matrix metalloproteinase; SCFA, short chain fatty acid. Figure created with BioRender.
See this image and copyright information in PMC

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