Therapeutic modulation of phagocytosis in glioblastoma can activate both innate and adaptive antitumour immunity

Christina A. Roemeling, Yifan Wang, Yaqing Qie, Hengfeng Yuan, Hai Zhao, Xiujie Liu, Zhaogang Yang, Mingming Yang, Weiye Deng, Katelyn A. Bruno, Charles K. Chan, Andrew S. Lee, Stephen S. Rosenfeld, Kyuson Yun, Aaron J. Johnson, Duane A. Mitchell, Wen Jiang () and Betty Y. S. Kim ()
Additional contact information
Christina A. Roemeling: Mayo Clinic
Yifan Wang: The University of Texas Southwestern Medical Center
Yaqing Qie: Mayo Clinic
Hengfeng Yuan: Mayo Clinic
Hai Zhao: The University of Texas MD Anderson Cancer Center
Xiujie Liu: Mayo Clinic
Zhaogang Yang: The University of Texas Southwestern Medical Center
Mingming Yang: The University of Texas Southwestern Medical Center
Weiye Deng: The University of Texas Southwestern Medical Center
Katelyn A. Bruno: Mayo Clinic
Charles K. Chan: Stanford University
Andrew S. Lee: Stanford School of Medicine
Stephen S. Rosenfeld: Mayo Clinic
Kyuson Yun: Houston Methodist Research Institute
Aaron J. Johnson: Mayo Clinic
Duane A. Mitchell: University of Florida
Wen Jiang: The University of Texas Southwestern Medical Center
Betty Y. S. Kim: Mayo Clinic

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Tumour cell phagocytosis by antigen presenting cells (APCs) is critical to the generation of antitumour immunity. However, cancer cells can evade phagocytosis by upregulating anti-phagocytosis molecule CD47. Here, we show that CD47 blockade alone is inefficient in stimulating glioma cell phagocytosis. However, combining CD47 blockade with temozolomide results in a significant pro-phagocytosis effect due to the latter’s ability to induce endoplasmic reticulum stress response. Increased tumour cell phagocytosis subsequently enhances antigen cross-presentation and activation of cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) in APCs, resulting in more efficient T cell priming. This bridging of innate and adaptive responses inhibits glioma growth, but also activates immune checkpoint. Sequential administration of an anti-PD1 antibody overcomes this potential adaptive resistance. Together, these findings reveal a dynamic relationship between innate and adaptive immune regulation in tumours and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses.

Date: 2020
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DOI: 10.1038/s41467-020-15129-8

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