To improve the antitumor immunity of in situ vaccination using radiation therapy (RT) combined with immune checkpoint blockade (ICB), Zhang, Srirameni et al. tested a scalable nanoparticle consisting of polylysine, iron oxide, and CpG (PIC) that was designed to down-modulate TME suppression. When combined with RT and ICB, PIC enhanced in situ vaccine RT efficacy, and primed a potent systemic antitumor response with cures and long-term memory in several syngeneic “cold” tumor models. PIC addition increased tumor antigen presentation by DCs, increased the M1:M2 TAM ratio, antagonized the RT-induced increase in Tregs, and stimulated a type 1 interferon response.
Contributed by Katherine Turner
ABSTRACT: Radiation therapy (RT) activates an in situ vaccine effect when combined with immune checkpoint blockade (ICB), yet this effect may be limited because RT does not fully optimize tumor antigen presentation or fully overcome suppressive mechanisms in the tumor-immune microenvironment. To overcome this, we develop a multifunctional nanoparticle composed of polylysine, iron oxide, and CpG (PIC) to increase tumor antigen presentation, increase the ratio of M1:M2 tumor-associated macrophages, and enhance stimulation of a type I interferon response in conjunction with RT. In syngeneic immunologically "cold" murine tumor models, the combination of RT, PIC, and ICB significantly improves tumor response and overall survival resulting in cure of many mice and consistent activation of tumor-specific immune memory. Combining RT with PIC to elicit a robust in situ vaccine effect presents a simple and readily translatable strategy to potentiate adaptive anti-tumor immunity and augment response to ICB or potentially other immunotherapies.
Author Info: (1) Department of Biomedical Engineering and Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA. Department of Ophthalmology and Visual Sciences,
Author Info: (1) Department of Biomedical Engineering and Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA. Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA. (2) Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, USA. (3) Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, USA. (4) Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, USA. (5) Department of Biomedical Engineering and Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA. Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA. (6) Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, USA. (7) Department of Biomedical Engineering and Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA. Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA. (8) Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, USA. (9) Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, USA. Department of Radiology, University of Wisconsin-Madison, Madison, WI, USA. (10) Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA. (11) Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, USA. (12) Department of Biomedical Engineering and Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA. Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA. (13) Department of Biomedical Engineering and Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA. Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA. (14) Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA. (15) Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, USA. (16) Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, USA. (17) Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA. (18) Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA. (19) Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, USA. Department of Pediatrics, University of Wisconsin-Madison, Madison, WI, USA. (20) Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA. (21) Department of Biomedical Engineering and Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA. shaoqingong@wisc.edu. Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA. shaoqingong@wisc.edu. (22) Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, USA. zmorris@humonc.wisc.edu.
