Dying Right: Supporting Anti-Cancer Therapy Through Immunogenic Cell Death

Author

Elizabeth Schmitz, University of Nebraska Medical CenterFollow

ORCID ID

0000-0002-9619-5193

Graduation Date

Summer 8-9-2024

Document Type

Thesis

Degree Name

Master of Science (MS)

Programs

Cancer Research

First Advisor

Dalia El-Gamal, MSc, PhD

Second Advisor

Joyce Solheim, PhD

Third Advisor

Amarnath Natarajan, PhD

Abstract

The primary goal of most anti-cancer therapy is to eradicate neoplastic cells. Simultaneously, neoplastic cell death is the first step of the cancer-immunity cycle, which starts with the release of antigens from cancer cells and ends with T-cell directed killing of cancer cells, in addition to long-standing memory to tumor antigens encountered. Immunogenic damage-associated-molecular patterns (DAMPs) are endogenous cell molecules repurposed in times of insurmountable cell stress (e.g., CALR, ATP, HMGB1) to facilitate communication between dying cells and adaptive immune cells, acting as adjuvants for the cancer-immunity cycle, in a cellular fate termed immunogenic cell death (ICD). It is hypothesized that immunogenic DAMP release, and thus ICD, can be induced through focal endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation. Previously, our lab has investigated how a three-carbon-linker spirocyclic dimer (SpiD3) promotes futile activation of the unfoleded protein response (UPR) in chronic lymphocytic leukemia (CLL) cells through immense misfolded-protein mimicry, culminating to insurmountable ER stress and programmed cell death¹. In turn, we hypothesize that this insurmountable ER stress may confer SpiD3 the unique ability to promote immunogenic DAMP release and propagate ICD in B-cell malignancies, such as CLL. Through the course of this project, we use CLL as a disease model to consider the relationship between novel therapeutics, manners of cancer cell death, and their contributions to adaptive immune cell engagement, as a means for improving anti-cancer therapy.

Comments

2024 Copyright, the authors

Recommended Citation

Schmitz, Elizabeth, "Dying Right: Supporting Anti-Cancer Therapy Through Immunogenic Cell Death" (2024). Theses & Dissertations. 846.
https://digitalcommons.unmc.edu/etd/846