In recent years, checkpoint blockade has been used successfully to treat many cancer types including melanoma, non-small cell lung, and colorectal cancers. In stark contrast, the response to these new immunotherapeutics has been poor in patients with pancreatic ductal adenocarcinoma (PDAC), the most common and lethal type of pancreatic cancer. Thus, PDAC is considered a cold tumor for immunotherapy and the mechanism underlying this resistance is poorly understood. Insulin-like growth factor binding protein-2 (IGFBP2), a secreted cytokine, is elevated in the serum, pancreatic juice, and PDAC tissues in many pancreatic cancer patients, and we demonstrated that high levels associate to reduced overall patient survival and promote the immunosuppressive M2 tumor-associated macrophage phenotype in the tumor microenvironment (TME). We recently identified IGFBP2 as a key oncogenic signaling molecule for PDAC metastasis and epithelial-to-mesenchymal transition. Our preliminary microarray analysis showed that major histocompatibility complex class II antigen (MHC class II) genes were significantly downregulated in AsPC-1 pancreatic cancer cells overexpressing IGFBP2. MHC class II molecules are constitutively expressed in antigen-presenting cells (APCs) such as dendritic and Langerhans cells, macrophages, and B lymphocytes. In PDAC, increased MHC class II expression correlates to a higher histologic grade of differentiation. Also, CD4+ T lymphocyte numbers in PDAC tissues positively correlate to MHC class II expression levels. We envision that high IGFBP2 represses MHC class II gene expression in the tumor-associated APCs, resulting in failure of recruitment and activation of CD4+ lymphocytes, augmenting the immunosuppressive TME. The mechanism whereby IGFBP2 regulates MHC class II gene expression, however, is unknown. IGFBP2 was reported to physically interact with Pim-1-associated protein-1 (PAP-1)-associated protin-1 (PAPA-1) in the nucleus. PAPA-1 (or INO80B) is a key component in the ATP-dependent INO80 chromatin-remodeling complex. A recent study shows that INO80 is required for super-enhancer-mediated oncogenic transcription and tumor growth in melanoma. Interestingly, the MHC class II genes HLA-DR and HLA-DQ were found to be regulated by a super-enhancer mediated mechanism in autoimmune disease. We hypothesized that tumor-secreted IGFBP2 directly regulates INO80 function and inhibits the MHC class II expression in APCs in the TME. Our preliminary data show that exogenous IGFBP2 translocates into the cell nucleus within hours, and co-immunoprecipitation confirmed that IGFBP2 interacts with INO80B in vitro. Furthermore, MHC Class II expression was downregulated by IGFBP2 in the murine DC 2.4 dendritic cell line and in mouse bone marrow-derived dendritic cells by RT-PCR and flow cytometry. Our data suggest that PDAC IGFBP2 levels might predict checkpoint blockade therapy readiness, and importantly, serve as a target mechanism for enabling immunotherapy effectiveness.
Citation Format: Ping-Chieh Chou, Liang Liu, Elizabeth Forbes, Ashley Ballard, Tao Li, Wei Zhang. IGFBP2 reprograms pancreatic cancer immune surveillance at epitranscriptome levels [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B98.