Generation of an In Situ Tumor Vaccine Using Focused Ultrasound-Induced Immune Priming

Abstract

The goal of cancer treatment is to destroy all malignant cells within the patient's body, thereby preventing metastases or recurrence. This destruction can be achieved, in broad terms, by direct killing of the cells with a chemical or mechanical agent or by harnessing the power of the patient's immune system, using immunotherapy. Immune activation against tumors often fails because of a dearth of antigenic stimulus for the immune system and defective antigen presentation. How the innate antigen presenting cells interact with dying tumor cells and the mechanism of tumor cell death determines whether the immune system will be activated after tumor ablation to potentiate tumor immunotherapy. Through a combination of targeted therapies, we can achieve immunogenic cell death, which invigorates the immune system to attack the malignant cells and prevent dissemination. Low intensity focused ultrasound (LoFU) is a noninvasive, nontoxic, confocal therapy, delivering sonic stress. LoFU significantly alters expression and localization of heat shock proteins, which are highly conserved molecules that are rapidly upregulated in times of stress to encourage cell survival or promote a robust immune response and enhance cross-presentation to CD8+ T cells. Here, we demonstrate that treatment of murine solid tumors, including breast and prostate tumors, with LoFU followed by radiation therapy results in primary tumor cure and upregulation of the immune response. Through these noninvasive therapies, we are able to generate an in situ vaccine, generating CD8+ T cells against tumor-associated antigens and providing a viable oncologic treatment option for other tumor models.