Abstract
Tumors can escape from the immune system by overexpressing CD47 and other checkpoint blockades. CD47 is expressed ubiquitously by all cells in the body, posing an obstacle for CD47 blocking treatments due to their systemic toxicity. We performed a study to determine how the tumor microenvironment changes after vaccination with genome edited CD47−/− syngeneic tumor cells. We discovered that inactivated CD47-depleted mouse melanoma cells can protect mice from melanoma. Our animal study indicated that 33% of vaccinated mice remained tumor-free, and 100% of mice had 5-fold reduced growth rates. The characterization of immunomodulatory effects of the vaccine revealed a highly anti-tumorigenic and homogenous microenvironment after vaccination. We observed consistently that in the tumors that failed to respond to vaccines, there were reduced natural killer cells, elevated regulatory T cells, M2-type macrophages, and high PD-L1 expression in these cells. These observations suggested that the tumor microenvironments became more suppressive to tumor growth after vaccination, suggesting a potential new immunotherapy for solid tumors.
Highlights
Cancer cells possess a plethora of immune evasion mechanisms in reaction to specific immune responses[1,2]
We hypothesized that (i) providing the immune system with non-replicating tumor cells would circumvent the need for tumor-associated antigen (TAA) profiling, protein purification, viral packaging, and other preparation regimes[26,27]; and (ii) targeting the cycle upstream of T cell activation would lead to a lasting response that can be utilized in subsequent therapies
The use of inactivated non-replicating tumor cells as vaccines utilizes the immunogenic potential of whole tumor cells leading us to hypothesize that cell-surface CD47 depletion can unmask whole-cell vaccines to the immune system effectively
Summary
Cancer cells possess a plethora of immune evasion mechanisms in reaction to specific immune responses[1,2]. Various studies have shown that the depletion of CD47 expression on cancer cells using either siRNA31,32 or genetic editing has proven effective in slowing down tumor growth and enhancing phagocytosis by macrophages[34,37] These studies have been essential understanding the role of CD47 in tumor immunology, and have yielded a number of formulations for combinatorial approaches[33,34,36,38,39]. These macrophages are capable of recognizing and phagocytosing the CD47-null tumor cells and presenting antigens effectively to T cells, leading to the development of a robust downstream immune response This will further lead to increased infiltration of primed tumor-specific cytotoxic T cells into the microenvironment of the growing tumor, resulting in tumor shrinkage or blockade of tumor growth.
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