Radiation combines with immune checkpoint blockade to enhance T cell priming in a murine model of poorly immunogenic pancreatic cancer.

Courtney T Stump,Nataly Manjarrez Orduno,Stephanie K Dougan,Kevin Roehle

doi:10.1098/rsob.210245

Abstract

Radiation has been a pillar of cancer therapy for decades. The effects of radiation on the anti-tumour immune response are variable across studies and have not been explicitly defined in poorly immunogenic tumour types. Here, we employed combination checkpoint blockade immunotherapy with stereotactic body radiation therapy and examined the effect on tumour growth and immune infiltrates in subcutaneous and orthotopic mouse models of pancreatic cancer. Although immune checkpoint blockade and radiation were ineffective alone, their combination produced a modest growth delay in both irradiated and non-irradiated tumours that corresponded with significant increases in CD8+ T cells, CD4+ T cells and tumour-specific T cells as identified by IFNγ ELISpot. We conclude that radiation enhances priming of tumour-specific T cells in poorly immunogenic tumours and that the frequency of these T cells can be further increased by combination with immune checkpoint blockade.

Highlights

Though survival varies based on cancer stage and type, 85% of pancreatic cancer patients are diagnosed with pancreatic ductal adenocarcinoma (PDAC) and are diagnosed post-metastatic spread [2]
Radiation exerts both immune-promoting and immunesuppressing effects, which complicates its use in combination immunotherapy regimens
We combined dual PD-1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade with radiation in a poorly immunogenic model of pancreatic cancer and found that the combination therapy augments tumour-specific T cell priming. These findings are consistent with a phase II trial that evaluated two dosing regimens of stereotactic beam radiotherapy (SBRT) combined with either durvalumab or durvalumab plus tremelimumab [49]

Summary

Introduction

Pancreatic malignancies remain among the deadliest cancers, with an overall survival rate under 10% [1]. Though survival varies based on cancer stage and type, 85% of pancreatic cancer patients are diagnosed with pancreatic ductal adenocarcinoma (PDAC) and are diagnosed post-metastatic spread [2]. PDAC is characterized by dense fibrotic stroma consisting of fibroblasts, extracellular matrix, macrophages, granulocytes and monocytes, which collectively form an immunosuppressive microenvironment [2,5]. Both CD4+ and CD8+ T cells are present in pancreatic cancer, they are frequently located away from the tumour cell nests. Tumour cells are more commonly found in close proximity to alternatively activated macrophages or fibroblasts, both of which portend poor prognosis [6,7,8,9]

Methods

Results

Conclusion