Modulation of the Human Pancreatic Ductal Adenocarcinoma Immune Microenvironment by Stereotactic Body Radiotherapy

Stereotactic body radiotherapy (SBRT) uses multiple targeted beams of radiation to damage malignant cells while limiting effects to surrounding tissue. SBRT is a standard treatment for various cancers that elicit strong immune responses, but immunologically cold tumors, such as pancreatic ductal adenocarcinoma (PDAC), are often refractory. SBRT has been shown to promote opposing antitumor and immunosuppressive effects in mouse models of PDAC, though it is unknown if a similar dynamic limits SBRT efficacy in humans. 

This study characterized the immunomodulatory effect of SBRT on the tumor microenvironment (TME) of human PDAC using immunohistochemistry (IHC), RNA-seq, and T-cell receptor β-chain sequencing. Tumor samples were obtained from patients with resectable PDAC who received SBRT a median of seven days before surgery, and IHC slides were scanned on a Vectra Polaris scanner.  

After imaging, a licensed pathologist annotated the tumoral and adjacent peritumoral regions and a random forest classifier was trained to annotate regions of dense collagen, tertiary lymphoid structures (TLS), vasculature, and tumor nests using the HALO® Tissue Classifier Add-on. The Highplex FL module was utilized to quantify immune, tumor, and vascular endothelial cells on the IHC slides and within specific regions annotated by the classifier. The authors performed nearest neighbor, proximity, and heatmap analysis of immune, vascular, and tumor cells using the Spatial Analysis module. 

Mills et al observed that SBRT treatment decreased tumor cell densities and did not result in T-cell sequestration in fibrotic regions or alter PDAC vasculature. Further analysis indicated that SBRT PDAC samples exhibited TLS remodeling and increased percentages of PD-1+ effector cells but exhibited no change in the ratio of myeloid suppressors to effector cells (approximately 100:1). 

The authors conclude that SBRT is a promising method for generating an immunogenic response against PDAC but is limited as a monotherapy by refractory immune suppression mechanisms in the TME. Combining SBRT with immunotherapy could counter this suppression and capitalize on the antitumor immune priming effect of SBRT for the treatment of PDAC. 

Mills B, Qiu H, Drage M, Chen C, Mathew J, Garrett-Larsen J, Ye J, Uccello T, Murphy J, Belt B, Lord E, Katz A, Linehan D, Gerber S 

Clinical Cancer Research | First published 3 December 2021 | DOI 

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