Rao et al. showed that antitumor responses to irradiation (IR) are greatly enhanced when all-trans retinoic acid (RA) is co-administered to mice. Within 4 days of combination IR and RA treatment, increased intratumoral levels of iNOS- and TNF-α-expressing macrophages (Inf-MACS) were observed. This was followed by iNOS-dependent enhanced recruitment of tumor-specific CD4+ and CD8+ effector cells – both important contributors to the response. Inf-MACs and T cells function in a synergistic feedback loop to maintain a pro-inflammatory TME. PD-L1 blockade enhanced combination therapy, even in tumors distal to an irradiated tumor.
Contributed by Margot O’Toole
ABSTRACT: Radiotherapy is an important anticancer treatment modality that activates innate and adaptive immune responses. When all-trans retinoic acid (RA) was administered with radiation, we observed superior antitumor responses compared with ionizing radiation (IR) alone or RA alone. The superior antitumor effects of combination treatment were accompanied by a marked increase of tumor necrosis factor–α– and inducible nitric oxide synthase–producing inflammatory macrophages in local and distal nonirradiated tumors. Inflammatory macrophages are essential for the therapeutic efficacy of combination treatment by inducing effector T cell infiltration and enhancing the effector T cell to regulatory T cell ratio in local and distal tumors. T cells and T cell–derived interferon-γ are crucial for increasing inflammatory macrophage levels in IR- and RA-treated tumors. Whereas CD8+ T cells are required for the antitumor response to IR, CD4+ T cells are required for the effectiveness of the IR + RA combination. Combination treatment with RA enhanced the abscopal response when radiation and programmed cell death-ligand 1 blockade were used together. The synergistic positive feedback loop of inflammatory macrophages and adaptive immunity is required for the antitumor efficacy of IR + RA combination treatment. Our findings provide a translational and relatively nontoxic strategy for enhancing the local and systemic antitumor effects of IR.
Author Info: (1) Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China. (2) Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
Author Info: (1) Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China. (2) Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China. (3) Ludwig Center for Metastasis Research, Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA. (4) Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, ShaanXi 710061, China. (5) Department of Oncology, First Affiliated Hospital with Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong 250014, China. (6) Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL, USA. (7) Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250014, China. (8) Department of Medicine, University of Chicago, Chicago, IL, USA. (9) Department of Pathology, University of Texas Southwest Medical Center, Dallas, TX, USA. *Corresponding author. Email: rrw@radonc.uchicago.edu (R.R.W.); hualiang@uchicago.edu (H.L.L.)† These authors contributed equally to this work.
