Low Intensity Focused Ultrasound (LOFU)-mediated Acoustic Immune Priming and Ablative Radiation Therapy for in situ Tumor Vaccines

Karin A Skalina,Chandan Guha,Fernando Macian,Saurabh Singh,Claudia Gutierrez Chavez

doi:10.1038/s41598-019-51332-4

Abstract

Focal ablative therapies have been primarily used for local tumor ablation. However, they often fail to impact systemic disease. Here we propose the use of low intensity focused ultrasound (LOFU), a noninvasive, nontoxic, conformal therapy, to deliver acoustic stress to the tumor for immune priming. We demonstrate that LOFU significantly induces expression and cell surface localization of heat shock proteins in murine breast (4T1) and prostate adenocarcinoma (TPSA23) cancer cell lines. In vivo LOFU followed by ablative radiation therapy (RT) results in primary tumor cure, upregulation of a cytotoxic immune response and induction of immunological memory by inhibiting secondary tumor growth upon re-challenge with tumor cells. We, therefore, describe a regimen of a combination therapy with noninvasive, acoustic immune priming and ablative radiation therapy to generate an in situ tumor vaccine, induce CD8+ T cells against tumor-associated antigens and provide a viable oncologic treatment option for solid tumors.

Highlights

HIFU has been recently approved by the Food & Drug Administration (FDA) for the ablation of prostate tissue, including localized prostate cancer, which is the second leading cause of cancer-related deaths in the United States[4,5]
Cell surface HSP70 increased after treatment with 5 W, 50% duty cycle (7.3% of cells having surface HSP70 compared to 4.8% in non-treated)
We demonstrate that low intensity focused ultrasound (LOFU)-mediated immune priming stimulated a robust heat shock response with an increase in RNA, protein expression, and cell surface localization of heat shock proteins (HSP) in murine breast and prostate cancer cell lines

Summary

Introduction

HIFU has been recently approved by the Food & Drug Administration (FDA) for the ablation of prostate tissue, including localized prostate cancer, which is the second leading cause of cancer-related deaths in the United States[4,5]. HIFU causes instantaneous necrotic cell death at the focal point and the release of denatured proteins from these cells might not be efficient at generating a robust anti-tumoral T helper 1 (Th1) and cytotoxic T cell (CTL) mediated immune response. We hypothesized that LOFU-mediated immune priming of tumors, followed by ablative RT should increase the release of tumor-derived HSP-peptide complexes that could promote antigen cross-presentation and activation of CD8+ T cells for the induction of systemic anti-tumoral immunity. We demonstrate that LOFU induces a heat shock protein response in murine breast and prostate cancer cell lines and the combination therapy of LOFU and ablative RT controls primary murine prostate cancer, while increasing anti-tumoral cytotoxic T cell response and immune memory in a murine prostate cancer model

Objectives

Methods

Results

Conclusion