Pancreatic ductal adenocarcinoma (PDAC) is considered non-immunogenic, with trials showing its recalcitrance to PD1 and CTLA4 immune checkpoint therapies (ICTs). This is partly due to the time’s immunosuppressive conditions, but the mechanisms behind this resistance are not fully understood.
In a new study, researchers at The University of Texas MD Anderson Cancer Center have discovered a novel immunotherapy combination, targeting checkpoints in both T cells and myeloid suppressor cells, that successfully reprogrammed the tumor immune microenvironment (TIME) and significantly improved antitumor responses in preclinical models of pancreatic cancer.
Using high-dimensional immune profiling in mouse and human pancreatic cancers, scientists carefully examined mechanisms of immunotherapy resistance. They also determined potential therapeutic targets.
They discovered that blocking many different TIME immunosuppressive processes significantly increased survival rates in lab animals, suggesting a potential therapeutic approach for this highly deadly and resistant cancer.
Corresponding author Ronald DePinho, M.D., professor of Cancer Biology, said, “This triple combination therapy led to an unprecedented curative response in our models. The prevailing view has been that pancreatic cancer is impervious to immunotherapy, but this preclinical study shows that it can be vulnerable to the right combination therapy. Moreover, the presence of these targets in human pancreatic cancer specimens raises the possibility that such therapeutic combinations could one day help our patients.”
To investigate how various immunotherapies influence the TIME, the researchers performed single-cell RNA sequencing and high-dimensional immunological profiling. They discovered two particular immunological checkpoint proteins that were substantially expressed in worn-out T cells: 41BB and LAG.
When researchers tested antibodies targeting these checkpoints, they found that models treated with a 41BB agonist and LAG3 antagonist had slower tumor progression, higher levels of antitumor immunity indicators, and significantly higher survival rates than treatment with either antibody alone or with other checkpoint inhibitors. Notably, the absence of efficacy of anti-PD1 or anti-CTLA-4 therapy in these preclinical investigations closely matched the human data.
The researchers confirmed the presence of these two therapeutic targets in human pancreatic cancer samples and found that 81% and 93% of the patients studied had T cells expressing LAG3 and 41BB, respectively.
The researchers also looked at attempts to reprogramme the TIME to make tumors more sensitive to immunotherapy because this dual-therapy combo did not entirely eradicate established cancers. Many myeloid-derived suppressor cells (MDSCs) expressed CXCR2, a protein linked to attracting immunosuppressive cells, were present in the TIME at baseline. CXCR2 inhibition prevented tumor development and reduced MDSC migration; however, it was not curative. The researchers were encouraged to develop a combination targeting 41BB, LAG3, and CXCR2.
This triple combination resulted in complete tumor regression and improved overall survival in 90% of preclinical models. In a more stringent lab model that develops multiple spontaneously arising tumors with higher treatment resistance, the combination achieved complete tumor regression in over 20% of cases.
Corresponding author Ronald DePinho, M.D., professor of Cancer Biology, said, “These are encouraging results, especially considering the lack of effective immunotherapy options in pancreatic cancer. By targeting multiple synergistic mechanisms that get in the way of the immune response, we can give T cells a fighting chance to attack these tumors. Of course, we still need to see how this combination translates into a safe and effective regimen in the clinic, and we invite other researchers to build upon these results. We are optimistic that pancreatic cancers, and hopefully other non-immunogenic cancers, can ultimately be rendered vulnerable to combination immunotherapy.”
Journal Reference:
- Pat Gulhati, Aislyn Schalck, Shan Jiang, et al. Targeting T cell checkpoints 41BB and LAG3 and myeloid cell CXCR1/CXCR2 results in antitumor immunity and durable response in pancreatic cancer. Nature Cancer, 2022; DOI: 10.1038/s43018-022-00500-z