Cho Lab Research

Cho Lab Overview

The Cho Lab is exploring ways to make immunotherapy a reality for patients with cancer.

The Cho Lab focuses on developing strategies to bring the remarkable benefits of immunotherapy to a wider range of patients with cancer. The success of contemporary cancer immunotherapy was enabled by the discovery that cancers engage proteins on immune cells to prematurely turn off their activity. By blocking these interactions, immunotherapy can prevent cancers from disabling immune cells, allowing the immune system to reject even advanced cancers. Importantly, for this to work, the immune system needs to at least initiate a response to cancer – an initial response that can then be augmented by immunotherapy. Unfortunately, many cancers – including most pancreatic, liver and intestinal cancers – are so invisible to the immune system that there is no initial response for immunotherapy to augment.

Developed at the University of Michigan, histotripsy is an entirely novel modality of focused ultrasound ablation capable of non-invasively destroying tumors with millimeter precision. Our laboratory has shown that histotripsy is capable of initiating anti-tumor immune responses. Indeed, in preclinical models, we have shown that histotripsy treatment of tumors triggers a systemic anti-tumor immune response strong enough to inhibit growth of distant, untreated tumors (the so-called abscopal effect). More importantly, we have shown that the anti-tumor immune response initiated by histotripsy can be magnified by immunotherapy – enabling us to experimentally treat resistant pancreatic and liver cancers with immunotherapy.

Clinical studies led by Dr. Cho and colleagues have led to the recent FDA approval of histotripsy for use in cancer patients. We are now fully engaged in the effort to optimally translate our laboratory findings into the clinic.

Preclinical models of histotripsy

In collaboration with Dr. Zhen Xu (University of Michigan Biomedical Engineering), we use small animal models of histotripsy to perform in vivo histotripsy tumor treatment of various cancers.

Preclinical models of immunotherapy

Our laboratory has established multiple small animal models of immunotherapy, using checkpoint inhibitors and other immunomodulators to treat a wide array of cancers known to be both sensitive and resistant to immune-based therapies.

Cell death and immune response assays

Using an array of techniques including cell culture, in vitro cell stimulation, flow cytometry, multiplex immunofluorescence, protein profiling and RNA sequencing, we have characterized the natural evolution of tumor microenvironmental changes caused by histotripsy, and the effects of those changes on cancer cell physiology, death, and the activation of innate and adaptive immune responses.

Histotripsy triggers immunogenic cell death.

Histotripsy causes a purely mechanical form of cell death, in which treated cancer cells release hidden tumor antigens. Because of its non-thermal nature, these antigens retain their conformational integrity without becoming denatured. We have learned that cancer cells adjacent to the ablation zone are also killed; however, these cells undergo a highly regulated pathway of cellular suicide called necroptosis. Necroptosis is a type of immunogenic cell death, so-called because cells die in a highly inflammatory manner, releasing not only their antigens, but substances called damage-associated molecular patterns that attract the attention of innate immune cells.

Histotripsy stimulates anti-tumor immune responses

Histotripsy tumor treatment is followed by a rapid influx of innate immune cells (macrophages, neutrophils, natural killer cells) into the ablation zone. These innate immune cells pick up released tumor antigen and traffic to tumor-draining lymph nodes, where they interact with and activate CD8+ T cells. These activated tumor-specific T cells then traffic into distant tumors. The ability of these T cells to kill cancer at distant sites explains the abscopal effects of histotripsy, where histotripsy treatment of tumors causes the spontaneous inhibition or regression of distant, untreated tumors. Tumor- infiltrating CD8+ T cells cause cancer cells to undergo a specific pathway of cell death called ferroptosis – a pattern of death mostly seen in cancer cells, and the mechanism responsible for the effects of cancer immunotherapy. Indeed, when we combine histotripsy with immunotherapy, the effects of immunotherapy are magnified.

Histotripsy radically alters the tumor microenvironment

We have observed that histotripsy causes an array of profound physiological changes within the tumor microenvironment. Tumors are normally very hypoxic, and the stress of low oxygen not only inhibits the function of immune cells, but increases the aggressiveness of cancer cells. Immediately following histotripsy, this hypoxia disappears. In addition, histotripsy rearranges the anatomy and function of blood vessels within tumors in ways that may facilitate the delivery of oxygen, immune cells, and even chemotherapy. We are learning that these physiological changes are highly important to the therapeutic effects of histotripsy.

As histotripsy is becoming a clinical reality for patients with cancer, the preclinical discoveries we have made are pointing to ways in which histotripsy could be used as an adjunct to immunotherapy. We hope to use the observations and mechanistic insights made in our laboratory to inform and design practical treatment strategies to improve outcomes for patients with all types of cancer.

We are coordinating translational studies to validate our preclinical observations in cancer patients treated with histotripsy. We are also developing clinical trials to optimally integrate histotripsy as a means of sensitizing patients to the benefits of immunotherapy.

Our lab maintains strong collaborations with a number of investigators and organizations. Currently, we're working closely with:

  • Faculty in the Department of Biomedical Engineering on combinatorial approaches using histotripsy and immunotherapy
  • Faculty in the Department of Medicine on the impact of histotripsy on inflammation
  • Faculty in the Department of Radiation Oncology comparing the immune effects of histotripsy and radiation therapy
  • Collaborators in pharmaceutical companies evaluating combinatorial strategies for histotripsy cancer treatments
  • Investigators at Peking University on immunotherapy for patients with liver cancer.
  • U.S Department of Veterans Affairs VA Merit Review Award: Re-engineering the tumor-draining lymph node to achieve memory T cell-based adoptive immunotherapy
  • National Institutes of Health National Cancer Institute, R01: Novel, noninvasive, rapid tumor ablation technology using histotripsy
  • University of Michigan Health System and Peking University Health Science Center Joint Institute for Translational and Clinical Research Award: Identification of tumoricidal T cell receptors from hepatocellular carcinoma-infiltrating CD8+ T lymphocytes
  • Histosonics–Michigan Corporate Relations Network: Histotripsy and immunotherapeutic response in the murine model
  • University of Michigan Rogel Cancer Center Forbes Institute for Cancer Discovery Grant: Hisotripsy tumor ablation: a trigger to expand the efficacy of cancer immunotherapy