Microparticles from tumors exposed to radiation promote immune evasion in part by PD-L1

Michael Timaner,Tal Kan,Ksenia Magidey,Yuval Shaked,Orit Kaidar-Person,Shahar Daniel,Alexander Nevelsky,Ruslana Kotsofruk,Tongwu Zhang,Robert S Kerbel,Dvir Shechter,Ziv Raviv,Elisabeth G E De Vries

doi:10.1038/s41388-019-0971-7

Abstract

Radiotherapy induces immune-related responses in cancer patients by various mechanisms. Here, we investigate the immunomodulatory role of tumor-derived microparticles (TMPs)—extracellular vesicles shed from tumor cells—following radiotherapy. We demonstrate that breast carcinoma cells exposed to radiation shed TMPs containing elevated levels of immune-modulating proteins, one of which is programmed death-ligand 1 (PD-L1). These TMPs inhibit cytotoxic T lymphocyte (CTL) activity both in vitro and in vivo, and thus promote tumor growth. Evidently, adoptive transfer of CTLs pre-cultured with TMPs from irradiated breast carcinoma cells increases tumor growth rates in mice recipients in comparison with control mice receiving CTLs pre-cultured with TMPs from untreated tumor cells. In addition, blocking the PD-1-PD-L1 axis, either genetically or pharmacologically, partially alleviates TMP-mediated inhibition of CTL activity, suggesting that the immunomodulatory effects of TMPs in response to radiotherapy is mediated, in part, by PD-L1. Overall, our findings provide mechanistic insights into the tumor immune surveillance state in response to radiotherapy and suggest a therapeutic synergy between radiotherapy and immune checkpoint inhibitors.

Highlights

These authors contributed : Michael Timaner, Ruslana Kotsofruk
We have previously shown that chemotherapy increases the production of tumor-derived microparticles (TMPs) originating from breast carcinoma cell lines, as well as from breast cancer patients [19]
To determine whether TMP production is affected by radiotherapy, EMT/6, 4T1, polyoma middle T-antigen (PyMT), E0771, and DA3 breast carcinoma cell cultures were exposed to a single fraction of 2 Gy or 6 Gy radiation, in accordance with clinically used doses

Summary

1234567890();,: 1234567890();,: Introduction

Tumors or metastatic sites that are outside of the irradiated field may respond positively to the radiation; such antitumor effects are rarely reported in the clinic This phenomenon, termed the “abscopal effect”, is due to extensive inflammation and activation of immune cells as a result of radiation [12, 13]. The role of TMPs in response to radiation and their possible contribution to immune cell activity at the irradiated tumor sites has not been studied. We show that TMPs from irradiated breast carcinoma cells contain high levels of an array of immunosuppressive proteins in comparison with TMPs derived from untreated cells These TMPs modulate the immune system, in part via PD-L1, resulting in enhanced tumor growth. Our study suggests that the expression of PD-L1 on TMPs could be useful as a possible biomarker to identify patients who are likely to benefit from the combination of radiotherapy with immune checkpoint therapy

Results

Discussion

Materials and methods

Compliance with ethical standards