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

Christina A Von Roemeling,Duane A Mitchell,Wen Jiang,Andrew S Lee,Hai Zhao,Kyuson Yun,Hengfeng Yuan,Weiye Deng,Zhaogang Yang,Xiujie Liu,Charles K Chan,Mingming Yang,Yaqing Qie,Katelyn A Bruno,Yifan Wang,Betty Y S Kim,Stephen S Rosenfeld,Aaron J Johnson

doi:10.1038/s41467-020-15129-8

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.

Highlights

Tumour cell phagocytosis by antigen presenting cells (APCs) is critical to the generation of antitumour immunity
To evaluate whether phagocytosis modulation promotes antitumour immune responses against poorly immunogenic tumors, we first evaluated whether CD47 is expressed in human and mouse glioblastoma (GBM), a malignant brain tumor
We found that glioma cells treated with TMZ transiently increased the translocation of the chaperone protein calreticulin, a pro-phagocytosis molecule that interacts with low density lipoprotein receptor-related protein 1 (LRP1)/CD91 receptor on phagocytes, from the ER lumen to the plasma membrane in a dose-dependent manner (Fig. 2a, b)

Summary

Introduction

Tumour cell phagocytosis by antigen presenting cells (APCs) is critical to the generation of antitumour immunity. 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, and activates immune checkpoint. Combining CD47 blockade with temozolomide (TMZ) results in a significant prophagocytosis effect and enhances antigen cross-presentation and activation of cGAS–STING in APCs, leading to more efficient priming of adaptive antitumour immune responses. Together, these results suggest targeting innate checkpoints that regulate phagocytosis represents a promising strategy to improve immunotherapy against immune suppressive tumors

Methods

Results

Conclusion