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Abstract
Background: Immune checkpoint inhibitors such as anti-programmed cell death protein 1 (PD1) block tumor growth by reinvigorating the immune system; however, determining their efficacy only by the changes in tumor size may prove inaccurate. As the immune cells including macrophages in the tumor microenvironment (TME) are associated with the response to anti-PD1 therapy, tumor-associated macrophages (TAMs) imaging using nanoparticles can noninvasively provide the immune enrichment status of TME. Herein, the mannosylated-serum albumin (MSA) nanoparticle was labeled with radioactive isotope 68Ga to target the mannose receptors on macrophages for noninvasive monitoring of the TME according to anti-PD1 therapy.

Results: B16F10-Luc and MC38-Luc tumor-bearing mice were treated with anti-PD1, and the response to anti-PD1 was determined by the tumor volume. According to the flow cytometry, the responders to anti-PD1 showed an increased proportion of TAMs, as well as lymphocytes, and the most enriched immune cell population in the TME was also TAMs. For noninvasive imaging of TAMs as a surrogate of immune cell augmentation in the TME via anti-PD1, we acquired [68Ga] Ga-MSA positron emission tomography. According to the imaging study, an increased number of TAMs in responders at the early phase of anti-PD1 treatment was observed in both B16F10-Luc and MC38-Luc tumor-bearing mice models.

Conclusion: As representative immune cells in the TME, non-invasive imaging of TAMs using MSA nanoparticles can reflect the immune cell enrichment status in the TME closely associated with the response to anti-PD1. As non-invasive imaging using MSA nanoparticles, this approach shows a potential to monitor and evaluate anti-tumor response to immune checkpoint inhibitors.

Affiliations

Gyo Jeong Gu 1, Hyewon Chung 1 2, Ji Yong Park 3 4, Ranji Yoo 3 5, Hyung-Jun Im 6 7, Hongyoon Choi 8 9 10, Yun-Sang Lee 11 12 13 14, Seung Hyeok Seok 15 16 17
1Macrophage Laboratory, Department of Microbiology and Immunology, Institute of Endemic Disease, Seoul National University College of Medicine, Seoul, Republic of Korea.
2Bio-MAX Institute, Seoul National University, Seoul, Republic of Korea.
3Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
4Dental Research Institute, Seoul National University, Seoul, Republic of Korea.
5Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
6Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.
7Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
8Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea. chy1000@snu.ac.kr.
9Radiation Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. chy1000@snu.ac.kr.
10Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea. chy1000@snu.ac.kr.
11Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea. wonza43@snu.ac.kr.
12Radiation Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. wonza43@snu.ac.kr.
13Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. wonza43@snu.ac.kr.
14Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea. wonza43@snu.ac.kr.
15Macrophage Laboratory, Department of Microbiology and Immunology, Institute of Endemic Disease, Seoul National University College of Medicine, Seoul, Republic of Korea. lamseok@snu.ac.kr.
16Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. lamseok@snu.ac.kr.
17Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea. lamseok@snu.ac.kr.