Abstract 3293: Exploiting PEGylation of CCN5 for tumor immunity and therapy of triple-negative breast cancer: A new and effective approach for TNBC therapy

Abstract Triple-negative breast cancer (TNBC) is defined by a lack of expressions of three receptors. These include estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor rector 2 (HER2). TNBC accounts for ∼15-17% of all breast cancers (BC) and is the most aggressive subtype of metastatic BC. TNBC incidence is high among BRCA1 mutation carriers, women with the age of 50 or below, and African American descent. The therapeutic opportunities for TNBC are limited to chemotherapy as targeted options are deficient, resulting in elevated risk of recurrence and mortality risk. Over the last five years, new strategies for treating TNBC have transformed significantly by introducing PD-1/PD-L1-immune checkpoint inhibitors (ICIs) and others. However, only eighteen-20% of PD-L1 positive TNBC patients with metastasis respond to ICIs with or without chemotherapy and enhance the antitumor response of therapeutic CD8+ T cells. The low overall response rate of ICIs in TNBC patients is due to insufficient PD-L1/PD-1 interaction blockade. Consequently, an unmet need exists to revolutionize treatment regimens by replacing or modifying them with ones that are more effective and less toxic. Previous studies demonstrate that CCN5 (also known as WISP-2), which is family of cellular communication Network (CCN) factors, is considered a tumor suppressor and anti-invasive protein as it promotes the growth arrest and progression of TNBC cells. Our previous studies showed that recombinant CCN5 (hrCCN5) therapy is weak for systemic delivery due to poor bioavailability. Thus, only intratumoral injection of CCN5 was considered and found effective with no toxicity in animal studies, but this is not an ideal therapeutic strategy for progressive BC therapy. To overcome this limitation, we implemented the protein PEGylation/PEG conjugation technique that increased the bioavailability and activities of CCN5 and reverses tumor growth and metastasis and increases prolonged overall survival in an MDA-MB-231tumor xenograft model. Further, we found that PEGCCN5 significantly increased CD8+ T cells decreased myeloid infiltration and PD-L1 expression in tumor cells. Thus, we consider PEGCCN5 can emerge as a new, beneficial immunotherapeutic drug for TNBC treatment alone or in combination with αPD-1, chemotherapy, or both. Citation Format: Sunil P. Upadhyay, Axel H. Breier, Inamul Haque, Archana De, Snigdha Banerjee, Mohiuddin Quadir, Sushanta K. Banerjee. Exploiting PEGylation of CCN5 for tumor immunity and therapy of triple-negative breast cancer: A new and effective approach for TNBC therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3293.