Intra-Tumoral Delivery of IL-27 Using Adeno-Associated Virus Stimulates Anti-tumor Immunity and Enhances the Efficacy of Immunotherapy.

Aiyan Hu,Xueliang Pan,Kalpana Ghoshal,Xue-Feng Bai,Miao Ding,Jianmin Zhu,Jin-Qing Liu

doi:10.3389/fcell.2020.00210

Abstract

IL-27 is an anti-inflammatory cytokine that has been shown to have potent anti-tumor activity. We recently reported that systemic delivery of IL-27 using recombinant adeno-associated virus (rAAV) induced depletion of Tregs and significantly enhanced the efficacy of cancer immunotherapy in a variety of mouse tumor models. A potential caveat of systemic delivery of IL-27 using rAAV is that there is no practical method to terminate IL-27 production when its biological activity is no longer needed. Therefore, in this work, we tested if directly injecting AAV-IL-27 into tumors could lead to similar anti-tumor effect yet avoiding uncontrolled IL-27 production. We found that high levels of IL-27 was produced in tumors and released to peripheral blood after AAV-IL-27 intra-tumoral injection. AAV-IL-27 local therapy showed potent anti-tumor activity in mice bearing plasmacytoma J558 tumors and modest anti-tumor activity in mice bearing B16.F10 tumors. Intra-tumoral injection of AAV-IL-27 induced infiltration of immune effectors including CD8+ T cells and NK cells into tumors, caused systemic reduction of Tregs and stimulated protective immunity. Mechanistically, we found that IL-27 induced T cell expression of CXCR3 in an IL-27R-dependent manner. Additionally, we found that AAV-IL-27 local therapy had significant synergy with anti-PD-1 or T cell adoptive transfer therapy. Importantly, in mice whose tumors were completely rejected, IL-27 serum levels were significantly reduced or diminished. Thus, intra-tumoral injection of AAV-IL-27 is a feasible approach that can be used alone and in combination with anti-PD-1 antibody or T cell adoptive transfer for the treatment of cancer.

Highlights

Cancer immunotherapies based on blockade of immune checkpoints (Phan et al, 2003; Topalian et al, 2012; Hamid et al, 2013) have achieved significant success
We tested if IL-27 expressing recombinant adenoassociated virus (rAAV) (AAV-IL27) infection of B16 cells could lead to IL-27 production
We previously found that i.m. injection of AAV-IL-27 could induce PD-L1 expression in T cells, which unexpectedly overcome tumor resistance to anti-PD-1 therapy (Zhu et al, 2018)

Summary

Introduction

Cancer immunotherapies based on blockade of immune checkpoints (Phan et al, 2003; Topalian et al, 2012; Hamid et al, 2013) have achieved significant success. Factors responsible for cancer resistance to immunotherapy are not fully understood, the AAV-IL-27 Intra-Tumoral Delivery for Cancer Therapy following factors are considered important. Lack of preexisting T cell infiltration in the tumor microenvironment (TME) is considered to be the most important factor for anti-PD1 resistance (Tumeh et al, 2014). Not wellestablished in human cancer, regulatory T cells (Tregs) in the TME contribute to anti-PD-1 resistance in mouse models (Ngiow et al, 2015). Not absolute, tumor expression of PD-L1 is another potentially important factor. In cancer types such as non-small cell lung carcinoma, bladder cancer and melanoma, PD-L1 immunohistochemistry has identified patients with a higher likelihood of treatment response (Topalian, 2017). Developing novel strategies that can overcome these limitations is critical to enhancing the efficacy of current cancer immunotherapies

Methods

Results

Conclusion