Enhanced Immunotherapy with LHRH-R Targeted Lytic Peptide in Ovarian Cancer

Kim, Mark Seungwook; Ma, Shaolin; Chelariu-Raicu, Anca; Leuschner, Carola; Alila, Hector W.; Lee, Sanghoon; Coleman, Robert L. und Sood, Anil K. (2020): Enhanced Immunotherapy with LHRH-R Targeted Lytic Peptide in Ovarian Cancer. In: Molecular Cancer Therapeutics, Bd. 19, Nr. 11: S. 2396-2406

Abstract

Here, we examined the role of EP-100 [luteinizing hormone-releasing hormone (LHRH) ligand joined to a lytic peptide], improving the efficacy of immune checkpoint blockade. LHRHR-positive murine ovarian cancer cells (ID8, IG10, IF5, and 2C12) were sensitive to EP-100 and were specifically killed at low micromolar levels through LHRH-R. EP-100 increased PD-L1 levels on murine ovarian cancer cells. In vivo syngeneic mouse models (ID8 and IG10) demonstrated that single-agent EP-100 reduced tumor volume, tumor weight, and ascites volume. The greatest reductions in tumor and ascites volume were observed with the combination of EP-100 with an anti-PD-L1 antibody. Immune profiling analysis showed that the population of CD8(+) T cells, natural killer cells, dendritic cells, and macrophages were significantly increased in tumor and ascitic fluid samples treated with anti-PD-L1, EP-100, and the combination. However, monocytic myeloid suppressor cells, B cells, and regulatory T cells were decreased in tumors treated with anti-PD-L1, EP-100, or the combination. In vitro cytokine arrays revealed that EP-100 induced IL1a, IL33, CCL20, VEGF, and Low-density lipoprotein receptor (LDLR) secretion. Of these, we validated increasing IL33 levels following EP-100 treatment in vitro and in vivo;we determined the specific biological role of CD8(+) T-cell activation with IL33 gene silencing using siRNA and Cas9-CRISPR approaches. In addition, we found that CD8(+) T cells expressed very low level of LHRH-R and were not affected by EP-100. Taken together, EP-100 treatment had a substantial antitumor efficacy, particularly in combination with an anti-PD-L1 antibody. These results warrant further clinical development of this combination.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1535-7163
• Sprache: Englisch