Anti-glucocorticoid-induced Tumor Necrosis Factor-Related Protein (GITR) Therapy Overcomes Radiation-Induced Treg Immunosuppression and Drives Abscopal Effects.

Jonathan E Schoenhals,Ailin Li,Hampartsoum B Barsoumian,Sharareh Niknam,Maria Angelica Cortez,Ahmed I Younes,Taylor R Cushman,Alexandra P Cadena,James W Welsh,Mauricio Da Silva Caetano

doi:10.3389/fimmu.2018.02170

Jonathan E Schoenhals, Ailin Li + Show 8 more

Open Access

https://doi.org/10.3389/fimmu.2018.02170

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Abstract

Despite the potential to cure metastatic disease, immunotherapy on its own often fails outright or early on due to tumor immune evasion. To address this obstacle, we investigated combinations of anti-GITR, anti-PD1 and radiation therapy (XRT) in our previously developed anti-PD1 resistant 344SQ non-small cell lung adenocarcinoma preclinical tumor model. We hypothesized that targeting multiple mechanisms of immune evasion with this triple therapy would lead to an enhanced tumor-specific immune response and improve survival more so than any mono- or dual therapy. In a two tumor 344SQR murine model, treatment with anti-GITR, anti-PD1, and XRT led to significantly improved survival and an abscopal response, with half of the mice becoming tumor free. These mice showed durable response and increased CD4+ and CD8+ effector memory on tumor rechallenge. Regulatory T cells (Tregs) expressed the highest level of GITR at the tumor site and anti-GITR therapy drastically diminished Tregs at the tumor site. Anti-tumor effects were largely dependent on CD4+ T cells and partially dependent on CD8+ T cells. Anti-GITR IgG2a demonstrated superior efficacy to anti-GITR IgG1 in driving antitumor effects. Collectively, these results suggest that combinatorial strategies targeting multiple points of tumor immune evasion may lead to a robust and lasting antitumor response.

Highlights

Lung cancer is the most common cancer worldwide, accounting for 1.69 million deaths annually [1]
To explore the mechanisms underlying treatment resistance, our lab recently developed an anti-PD1-resistant 344SQ nonsmall cell lung adenocarcinoma (NSCLC) cell line that is refractory to anti-PD1 treatment [5], and with this model we found that radiotherapy helps to overcome PD1 resistance by upregulating major histocompatibility complex (MHC) class I molecules
We previously showed that radiation can restore response to anti-PD1 [5] via upregulating MHC I, but we did not test this in an abscopal setting

Summary

Introduction

Lung cancer is the most common cancer worldwide, accounting for 1.69 million deaths annually [1]. For patients presenting with unresectable locally advanced disease, concurrent chemoradiation is the standard treatment for those who can tolerate it. This treatment regimen is relatively ineffective in terms of controlling metastasis, the cause of death for most patients with lung cancer. The benefit of radiation was previously thought to derive entirely from the reduction in tumor burden through improved local control. Improved understanding of the role of the immune system in regulating cancer has led to the recognition that radiation therapy is a potent cause of immunogenic cell death, serving to prime the immune system with the potential to attack cancer cells outside the irradiated area. Not all patients respond to immunotherapeutic agents, and even those who do often develop treatment resistance, when immunotherapeutics are given as monotherapy [3, 4]

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