Sensitizing pancreatic cancer to immunotherapy

Immunotherapy has become a game-changer for cancer treatments in the last decade, but some cancers, like pancreatic ductal adenocarcinoma (PDAC), can evade its antitumor activity.

“Unfortunately, less than five percent of pancreatic cancer patients respond to immunotherapy,” said Jiayun Li, a former postdoctoral scholar at Cold Spring Harbor Laboratory and coauthor of a new study investigating treatment options for PDAC (1). Widely considered one of the deadliest cancers, PDAC’s nonspecific symptoms and lack of screening options often lead to late detection and, with few effective treatments, only one in eight patients survives five years after diagnosis (2). Although the immune system can recognize and mount a response against pancreatic cancer cells, immune checkpoint inhibitor treatment rarely offers a survival benefit (3,4). PDAC’s ability to resist this treatment likely comes from its protective coating of CXC motif chemokine 12 (CXCL12), a cell membrane protein that prevents T cells from penetrating the tumor by sending chemical signals that repel the T cells (5,6).

“If T cells can get in, immune checkpoint inhibitors can act on the cancer,” Li explained. “This means immunotherapy could work in pancreatic cancer if we remodeled the immunosuppressive microenvironment to let T cells in.”

Penetrating PDAC’s defenses

Li and her colleagues turned to type I interferons. These signaling chemicals regulate many functions of the immune system; in cancer, they facilitate antitumor immune activity and enhance patients’ response to immunotherapy (7). Because type I interferon production is controlled by signals that originate from activated T cells, the researchers decided to focus on a type of T cell known as a natural killer T (NKT) cell that is activated very early in the immune response.

The researchers induced two types of PDAC in mice: tumors with normal PDAC features and genetically modified tumors incapable of forming a CXCL12 coating. Tumors without the CXCL12 coating were smaller than their unmodified counterparts and contained not only more NKT cells, but also higher numbers of other immune cells that participate in antitumor activity and fewer cells that suppress it. When the researchers grew the same tumor types in genetically engineered mice unable to produce NKT cells, the effect disappeared, demonstrating that the NKT cells are required for the antitumor response.

Additionally, tumors containing NKT cells showed greater expression of interferon-β — a type I interferon — and interferon-stimulated genes than tumors without. “We found that NKT cells enable type I interferon production within the pancreatic tumor, which initiates the antitumor immune response,” Li said.

Opening the door to NKTs

But understanding how NKT cells support antitumor immunity isn’t enough; for immune checkpoint inhibitors to work against PDAC, the researchers needed a way to get NKT cells past the CXCL12 barrier. Their original plan was to screen small molecule compounds to find one that induced NKT cell infiltration. Before they had the chance, though, they stumbled across a supplemental figure in a Science paper about NKT cell function that suggested folinic acid, a drug often used to make chemotherapy more effective or reduce its toxic side effects, might have the desired effect (8).

If T cells can get in, immune checkpoint inhibitors can act on the cancer. 
- Jiayun Li, Cold Spring Harbor Laboratory

After Li and her team treated PDAC mice with folinic acid, their tumors showed increased NKT cell numbers and upregulated type I interferon signaling. Although these effects alone did not slow tumor growth, adding an anti-PD-1 antibody — an immune checkpoint inhibitor effective in many cancers — halved the tumor growth rate in normal mice (9). In mice that lacked functioning NKT cells or type I interferon signaling, the treatment had no effect, further supporting the idea that these immune system components are required for effective immunotherapy.

These results show promise for immunotherapy’s potential in pancreatic cancer, but many questions remain. “There are still unknown aspects of NKT cell-based type I interferon regulation,” Li said. “We also need to see how our treatment works in humans who have tumor and immune heterogeneity, and how it works in metastatic pancreatic cancer because many patients are diagnosed with metastases already present.”

Jordan Winter, a pancreatic cancer researcher and surgical oncologist at Case Western Reserve University who was not involved in the study, agreed. “Mouse models are simplistic,” he said. “In the case of immunotherapy, the systems are dissimilar enough that success in mice may not translate into success in patients — but we won’t know until there are human trials.”

Fortunately, because folinic acid is part of numerous cancer treatment regimens, its safety and efficacy in humans has already been established (10). Li’s hope is that future research will examine the combination treatment’s effectiveness in human pancreatic tumors, allowing patients’ immune systems to mobilize against this previously resistant disease.

References

1. Li, J., Moresco, P., & Fearon, D.T. Intratumoral NKT cell accumulation promotes antitumor immunity in pancreatic cancer. Proc Natl Acad Sci USA  121, e2403917121 (2024).
2. National Cancer Institute. Pancreas: SEER 5-Year Relative Survival Rates, 2014–2020. (2024).
3. Yao, M. et al. Plasma cells in human pancreatic ductal adenocarcinoma secrete antibodies against self-antigens. JCI Insight  8, e172449 (2023).
4. Laface, C. et al. Immunotherapy and pancreatic cancer: a lost challenge?Life  13, 1482 (2023).
5. Wang, Z. et al. Carcinomas assemble a filamentous CXCL12-keratin-19 coating that suppresses T cell-mediated immune attack. Proc Natl Acad Sci USA  119, e2119463119 (2022).
6. Vianello, F. et al. Murine B16 melanomas expressing high levels of the chemokine stromal-derived factor-1/CXCL12 induce tumor-specific T cell chemorepulsion and escape from immune control. J Immunol  176, 2902–2914 (2006).
7. Yu, R., Zhu, B., and Chen, D. Type I interferon-mediated tumor immunity and its role in immunotherapy. Cell Mol Life Sci  79, 191 (2022).
8. Olszak, T. et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science  336, 489–493 (2012).
9. Liu, J. et al. PD-1/PD-L1 checkpoint inhibitors in tumor immunotherapy. Front Pharmacol  12, 731798 (2021).
10. Gristan, Y.D., Patel, P. & Moosavi, L. Folinic Acid. StatPearls (StatPearls Publishing, 2024).