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The ubiquitin-like protein, ISG15, is a novel tumor-associated antigen for cancer immunotherapy

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Abstract

The recent announcement of the first FDA-approved therapeutic vaccine for prostate cancer, Sipuleucel-T, is a watershed moment for the field of tumor immunotherapy. However, while Sipuleucel-T provides a powerful tool to clinicians for the most prevalent form of cancer in men, there remains an unmet need for a similar therapeutic strategy against breast cancer, the most prevalent cancer in women. While current breast cancer vaccines in development target several antigens, the most prevalent is the tumor-associated antigen, HER2. Initial results with HER2 vaccines appear promising in terms of efficacy; however, the lack of HER2 overexpression by a majority of breast tumors and the safety concerns associated with current HER2-targeted immunotherapy suggest that additional therapeutic strategies would be beneficial. Recently, several studies have identified ISG15 as a molecule highly expressed in numerous malignancies. ISG15 is a small ubiquitin-like protein regulated by type-I interferon and classically associated with viral defense. Elevated ISG15 expression in breast cancer is especially well documented and is independent of HER2, progesterone receptor, and estrogen receptor status. Additionally, high ISG15 expression in breast cancer correlates with an unfavorable prognosis and poor responses to traditional treatment strategies such as chemotherapy and radiation. To overcome these challenges, we employ a novel strategy to specifically target tumor-associated ISG15 expression with immunotherapy. We demonstrate that vaccination against ISG15 results in significant CD8-mediated reductions in both primary and metastatic mammary tumor burden. These results validate ISG15 as a tumor-associated antigen for cancer immunotherapy.

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Conflict of interest

Yvonne Paterson wishes to disclose that she has a financial interest in Advaxis, a vaccine and therapeutic company that has licensed or has an option to license all patents from the University of Pennsylvania that concern the use of Listeria monocytogenes or listerial products as vaccines.

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262_2011_1129_MOESM1_ESM.tif

Supplemental Fig 1. Therapeutic impact on mouse mammary primary and metastatic tumors with peptide vaccination against ISG15. a Tumor load study to determine the effectiveness of ISG15 peptide vaccination against primary implanted 4T1-Luc mammary tumors. 4T1-Luc tumor cells were implanted in the mammary tissue of BALB/c mice and subsequently vaccinated with either PBS alone or control CTL epitope and ISG15 CTL epitope peptides along with CpG ODN. Mean tumor volume and standard deviation of each treatment group over the course of the experiment are depicted. b 4T1-Luc lung metastatic burden after peptide vaccination. Mean number of lung metastatic lesions and standard deviation for each treatment group are depicted at experiment end. c Primary infection of ISG15 peptide vaccinated mice with wild-type Lm. Briefly, mice were administered either control or ISG15 peptide vaccine on day 1 and day 7. Subsequently, mice were infected i.p. with 1 x 105 CFUs wild-type Lm on day 14 and splenic Lm CFUs were determined on day 17. d Challenge infection with wild-type Lm after ISG15 peptide vaccination. Three groups of mice were initially vaccinated with an attenuated strain of Lm on day 1 and subsequently administered PBS, control peptide vaccine, or ISG15 peptide vaccine on day 30 and 37. Each group along with a naïve group of mice were challenged with 1 x 105 CFUs wild-type Lm on day 90 and splenic Lm CFUs determined on day 95. (TIFF 172 kb)

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Wood, L.M., Pan, ZK., Seavey, M.M. et al. The ubiquitin-like protein, ISG15, is a novel tumor-associated antigen for cancer immunotherapy. Cancer Immunol Immunother 61, 689–700 (2012). https://doi.org/10.1007/s00262-011-1129-9

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