Baylee J. O’Brien

 Background: Pancreatic ductal adenocarcinoma (PDAC) is cancer of the ductal cells of the pancreas and is projected to become the second leading cause of cancer related deaths by 2030¹. The low survival rate is largely due to the fibrotic stroma of the PDAC tumor microenvironment with infiltration of immunosuppressive M2 phenotype macrophages which presents challenges for chemotherapy and immunotherapy delivery^1,2. CD40 is a transmembrane receptor present on antigen presenting cells which has been shown to selectively reprogram tumor associated macrophages to promote an immune response³. Only 15% of patients diagnosed with PDAC are surgical candidates at time of diagnosis, and CD40 represents an emerging therapeutic target to improve patient outcomes⁴.

Objective: The goal of this review was to explore the mechanisms by which CD40 reprograms the pancreatic ductal adenocarcinoma tumor microenvironment.

Search Methods: An online search in the PubMed database was performed from 2018 to 2022 using the following keywords: pancreatic cancer, CD40, and tumor microenvironment.

Results: Studies have shown that upregulation of the CD40 receptor on antigen presenting cells in Trp53^flox/flox (KPC) mice with orthotopic intrapancreatic injections of PDAC cell lines demonstrated significantly reduced tumor growth rates compared to treatment naive controls³. To establish the mechanism of CD40 agonist mediated decrease in tumor growth rates, single cell RNA sequencing from 16 human PDAC samples revealed a higher expression of CD40 corresponded with an increase in the intratumoral Th1 cytokines IL-12 and IFN-⁵. Additionally, the analysis revealed CD40 expression promoted CD8+ T cell proliferation and enhanced MHC-I mediated antigen presentation⁵. Flow cytometry and single cell RNA sequencing analysis from KPC mice bone marrow cells demonstrated that CD40 agonist treatment resulted in significantly elevated expression of dendritic cell markers, CD80, CD86, and MHC-II⁵. Lastly, to determine if CD40 could reprogram tumor associated macrophages, a co-culture of PANC-1 cells with CD163+ M1 macrophages and HLA-DR M2 macrophages were treated with CD40 agonists⁶. The results showed a shift of polarization towards the M1 pro-inflammatory macrophage phenotype⁶. In emerging clinical trials, PDAC patients with significantly high M1 macrophages in the tumors had longer overall survival rates^7,8.

Conclusions: CD40 agonists promote antitumor activity in an IL-12 and IFN- dependent pathway. Treatment with CD40 agonists promotes maturation of dendritic cells to enhance antigen presentation and decreases tumor growth rates. Additionally, CD40 agonists modify the tumor microenvironment favoring an anti-tumor M1 macrophage differentiation. This identifies potential immunotherapy strategies to promote better clinical outcomes in PDAC patients.

Works Cited:

1. Pratt HG, Steinberger KJ, Mihalik NE, et al. Macrophage and Neutrophil Interactions in the Pancreatic Tumor Microenvironment Drive the Pathogenesis of Pancreatic Cancer. Cancers (Basel). 2021;14(1):194. Published 2021 Dec 31. doi:10.3390/cancers14010194
2. Storz P, Crawford HC. Carcinogenesis of Pancreatic Ductal Adenocarcinoma. Gastroenterology. 2020;158(8):2072-2081. doi:10.1053/j.gastro.2020.02.059
3. Jiang H, Courau T, Borison J, et al. Activating Immune Recognition in Pancreatic Ductal Adenocarcinoma via Autophagy Inhibition, MEK Blockade, and CD40 Agonism [published correction appears in Gastroenterology. 2022 Feb 7;:]. Gastroenterology. 2022;162(2):590-603.e14. doi:10.1053/j.gastro.2021.09.066
4. Singhi AD, Koay EJ, Chari ST, Maitra A. Early Detection of Pancreatic Cancer: Opportunities and Challenges. Gastroenterology. 2019;156(7):2024-2040. doi:10.1053/j.gastro.2019.01.259
5. Wang R, Chen J, Wang W, et al. CD40L-armed oncolytic herpes simplex virus suppresses pancreatic ductal adenocarcinoma by facilitating the tumor microenvironment favorable to cytotoxic T cell response in the syngeneic mouse model. J Immunother Cancer. 2022;10(1):e003809. doi:10.1136/jitc-2021-003809
6. Lim CY, Chang JH, Lee WS, Kim J, Park IY. CD40 Agonists Alter the Pancreatic Cancer Microenvironment by Shifting the Macrophage Phenotype toward M1 and Suppress Human Pancreatic Cancer in Organotypic Slice Cultures. Gut Liver. 2022;16(4):645-659. doi:10.5009/gnl210311
7. Padrón LJ, Maurer DM, O’Hara MH, et al. Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial. Nat Med. 2022;28(6):1167-1177. doi:10.1038/s41591-022-01829-9
8. Byrne KT, Betts CB, Mick R, et al. Neoadjuvant Selicrelumab, an Agonist CD40 Antibody, Induces Changes in the Tumor Microenvironment in Patients with Resectable Pancreatic Cancer. Clin Cancer Res. 2021;27(16):4574-4586. doi:10.1158/1078-0432.CCR-21-1047