Tadepalli and Clements et al. found that conformal radiotherapy (CRT; designed to limit normal tissue RT exposure) induced monocyte production of IFN-I independent of STING and recruited more monocytes to the tumors. Rather than becoming MDSCs or TAMs, these monocytes became activated, initiating antitumor responses from already-infiltrated effector T cells. CRT was more efficient than shield radiotherapy (SRT) at slowing tumor growth and improving survival in multiple murine models, likely due to SRT-induced damage to healthy tissues, which may more broadly distribute monocytes, leading to a TME marked by TAMs, Tregs, and exhausted T cells.
Contributed by Lauren Hitchings
ABSTRACT: The recruitment of monocytes and their differentiation into immunosuppressive cells is associated with the low efficacy of preclinical nonconformal radiotherapy (RT) for tumors. However, nonconformal RT (non-CRT) does not mimic clinical practice, and little is known about the role of monocytes after RT modes used in patients, such as conformal RT (CRT). Here, we investigated the acute immune response induced by after CRT. Contrary to non-CRT approaches, we found that CRT induces a rapid and robust recruitment of monocytes to the tumor that minimally differentiate into tumor-associated macrophages or dendritic cells but instead up-regulate major histocompatibility complex II and costimulatory molecules. We found that these large numbers of infiltrating monocytes are responsible for activating effector polyfunctional CD8(+) tumor-infiltrating lymphocytes that reduce tumor burden. Mechanistically, we show that monocyte-derived type I interferon is pivotal in promoting monocyte accumulation and immunostimulatory function in a positive feedback loop. We also demonstrate that monocyte accumulation in the tumor microenvironment is hindered when RT inadvertently affects healthy tissues, as occurs in non-CRT. Our results unravel the immunostimulatory function of monocytes during clinically relevant modes of RT and demonstrate that limiting the exposure of healthy tissues to radiation has a positive therapeutic effect on the overall antitumor immune response.
Author Info: (1) Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5101, USA. Immunology Program, Stanford University School of Medicine, Sta
Author Info: (1) Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5101, USA. Immunology Program, Stanford University School of Medicine, Stanford, CA 94304, USA. (2) Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5101, USA. Immunology Program, Stanford University School of Medicine, Stanford, CA 94304, USA. (3) Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5101, USA. Immunology Program, Stanford University School of Medicine, Stanford, CA 94304, USA. (4) Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5101, USA. Immunology Program, Stanford University School of Medicine, Stanford, CA 94304, USA. (5) Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5101, USA. Immunology Program, Stanford University School of Medicine, Stanford, CA 94304, USA. (6) Department of Biology, University of Prince Edward Island, Charlottetown, PE C1A 4P3, Canada. (7) Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. (8) Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5101, USA. Immunology Program, Stanford University School of Medicine, Stanford, CA 94304, USA. Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Redwood City, CA 94063, USA. (9) Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5101, USA. Immunology Program, Stanford University School of Medicine, Stanford, CA 94304, USA. Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA 94305-5101, USA. (10) Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5101, USA. Immunology Program, Stanford University School of Medicine, Stanford, CA 94304, USA. (11) Immunology Program, Stanford University School of Medicine, Stanford, CA 94304, USA. (12) Center for Cardiovascular Research, Departmental of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO 63110, USA. (13) Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (14) Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Institut Gustave Roussy, INSERM U1015, Btiment de Mdecine Molculaire, Villejuif 94800, France. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore 138648, Republic of Singapore. (15) Center for Cardiovascular Research, Departmental of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO 63110, USA. (16) Department of Biology, University of Prince Edward Island, Charlottetown, PE C1A 4P3, Canada. (17) Department of Nephrology, University Hospital Regensburg, Regensburg 93053, Germany. (18) Department of Radiation Oncology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA 94305-5101, USA. (19) Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5101, USA. Immunology Program, Stanford University School of Medicine, Stanford, CA 94304, USA.
