Listeria-Based Vaccines Targeting Interferon-Stimulated Gene 15 (ISG15) for Renal Cell Carcinoma and Colorectal Cancer

Abstract

<h3>Purpose/Objective(s)</h3> Interferon-stimulated gene 15 (ISG15) is the first identified ubiquitin-like modifier and has been implicated for its central role in innate immunity against intracellular pathogens. Since cancer cells oftentimes have defects in type I IFN signaling pathways, there is a growing body of evidence that demonstrated the role of ISG15 in cancer progression. Here, we investigate to understand if ISG15 could be another novel cancer-associated antigen in renal cell carcinomas (RCC) and colorectal cancer (CRC). Our research objectives include (i) to identify if the elevated expression of ISG15 in RCC and CRC has any prognosis signature, (ii) to explore if ISG15 can be targeted by mean of Listeria-based vaccines, and (iii) to analyze how Listeria-based vaccines targeting ISG15 change the tumor microenvironment of RCC and CRC in syngeneic mouse models. <h3>Materials/Methods</h3> Data on RNA and protein expression of ISG15 and the Kaplan–Meier survival analysis was obtained from Human Protein Atlas, The Cancer Genome Atlas, and from the University of Alabama at Birmingham, Comprehensive Cancer Center (UALCAN). RNA was extracted from tissue or cells and converted to cDNA. The cDNA was then subjected to qPCR analysis with primers specific to ISG15. All mouse experiments were performed in accordance with the regulations of the Institutional Animal Care and Use Committee (IACUC) at the TTUHSC. <h3>Results</h3> We found that the elevated expression of ISG15 in RCC and CRC is significantly associated with an unfavorable prognosis. Similarly, RCC and CRC murine cell lines also expressed a higher level of ISG15 compared to the normal fibroblast cell line. In subcutaneous syngeneic mouse models of RCC and CRC, vaccination with a Listeria-based vaccine targeting ISG15, designated Lm-LLO-ISG15, significantly controls primary tumor burden and extends median survival compared to control groups. In both models, treatment with Lm-LLO-ISG15 inflames the tumor microenvironment, enhances the influx of immune cells, and induces the expression of programmed cell death protein 1 (PD-1). <h3>Conclusion</h3> ISG15 is a novel cancer-associated antigen and a potential target for active immunotherapies such as Listeria-based vaccines. Treatment with Lm-LLO-ISG15 significantly controls tumor burden in both RCC and CRC syngeneic mouse models and sensitizes the tumors with anti-PD-1 therapies.