1. LaCorte, Sarah

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In the pursuit of new immunotherapies that will work for more patients and more cancer types, researchers have turned their attention to immune cell targets other than T cells.

Pancreatic cancer. P... - Click to enlarge in new windowPancreatic cancer. Pancreatic cancer

Vinod Balachandran, MD, a surgeon at Memorial Sloan Kettering Cancer Center and a team including cancer immunologists Taha Merghoub, PhD, and Jedd Wolchok, MD, PhD, identified promising anti-cancer function for group 2 innate lymphoid cells (ILC2s). ILC2s are newly discovered innate antigen-independent lymphocytes that regulate immunity and inflammation in a variety of human tissues. In a recent paper published in Nature, Balachandran's group used human tissue and mouse studies to show that ILC2s infiltrate pancreatic ductal adenocarcinomas (PDACs) to activate tissue-specific tumor immunity (2020; doi: 10.1038/s41586-020-2015-4).


"In pancreatic cancer, the vast majority of patients do not have a strong anti-cancer immune response. Because of this, current immunotherapies, which primarily work by boosting existing anti-cancer immunity in the tumor, are not effective," said Balachandran.

Vinod Balachandran, ... - Click to enlarge in new windowVinod Balachandran, MD. Vinod Balachandran, MD

A primary focus of Balachandran's research is to develop next-generation immunotherapies for pancreas cancer by identifying new ways to stimulate de novo anti-cancer immunity.


"The majority of pancreatic cancer patients have a weak immune response to their tumors, but a small subset, about nine percent of all pancreatic cancer patients, have strong immune response. Interestingly, these patients with stronger immune responses also survive much longer. My approach is to study these rare, long-term pancreatic cancer survivors and understand the basis of their tumor immunity," he said. "Our initial investigations suggested that tumors of long-term survivors may have higher densities of ILC2s."


The team looked in tumors from human pancreatic patients and found that ILC2s were expanded in tumors compared to nearby organs, as if they had multiplied in response to the tumor. In addition, they found that the patients whose tumors had more ILC2s had longer survival, suggesting this immune cell type may have anti-cancer function. Consistent with this, the team found that higher expression of the ILC2-activating cytokine interleukin 33 (IL33) in tumors, but not of any other ILC-activating cytokine, was also associated with longer survival and correlated with higher immune cytolytic activity in tumors.


The team then moved their studies to mouse models to mechanistically study the potential role of ILC2s in cancer immunity. Upon systemic administration of recombinant IL33, the ICL2-activating cytokine, the frequency of ILC2s was increased in mouse pancreatic tumors, but not in adjacent organs. Furthermore, tumor size was reduced and survival was improved with recombinant IL33 treatment compared to control. Importantly, the anti-cancer effects of recombinant IL33 treatment were reduced in genetically modified mice that lacked ILC2s, indicating that ILC2s were key mediators.


"We treated the mice with recombinant IL33 for 7 weeks so we could make sure the treatment continued to work and the cancer did not rebound after certain periods of time, and also to assess potential toxicity with repetitive administration. We were initially concerned that the mice could get quite ill with administering this recombinant cytokine for a longer duration but surprisingly they tolerated it very well. We think this is an encouraging preliminary result that supports IL33 as a potential immunotherapy," said Balachandran.


As ILC2s have tissue-specific phenotypes, the researchers hypothesized that ILC2 anti-cancer function in PDAC would also be tissue-specific. They treated mice with pancreas or subcutaneously implanted PDAC with recombinant IL33 and contrasted tumor growth. Pancreatic tumor ILC2s express the IL33 receptor, whereas skin ILC2s do not. Consistent with their prediction, IL33 prevented tumor establishment and prolonged survival in pancreas tumor PDAC mice, but did not prevent tumors in subcutaneous PDAC mice or expand SQ tumor ILC2s. These effects were also ILC2-dependent.


As activating tumor ILC2s had anti-tumor effects, the team then searched for strategies to further activate ILC2s. Using single-cell RNA sequencing, they found that the immune checkpoint protein PD-1 was the only detectable coinhibitory molecule expressed at baseline by tumor ILC2s. This suggested treating mice with IL33 may make pancreatic tumors sensitive to PD-1-blocking checkpoint inhibitors.


When the researchers gave recombinant IL33 plus a PD-1 inhibitor to mice with PDAC, there was a synergistic effect and maximal tumor control. Activating ILC2s by adding recombinant IL33 appeared to boost the ability for PD-1 checkpoint inhibitors to work well against the mouse pancreatic tumors. The team suggests a model where activated ILC2s send signals to recruit T cells to fight tumors.


The team hopes to translate these findings, and develop ILC2-activating approaches for the clinic. Thus far, pancreatic tumors have not responded well to anti-PD-1.


"Our next step is to identify ways to activate ILC2s in patients, and we are currently working on a variety of approaches for this, including IL33-based approaches. We think boosting tumor ILC2s alone or in combination with anti-PD-1 are promising strategies for pancreatic cancer that we hope to test clinically in the future. From a biology standpoint, we are beginning to learn more about what these cells do in cancers in different contexts and how they could be harnessed for immunotherapies.


"The main takeaway is that for cancer immunotherapy, ILC2s are the new kids on the block, and we don't fully understand their function in tumors. We think our study is pointing to the fact that, in at least in some tumors, they can have anti-tumor effects and boost immunity. We think further studies will clarify the role of ILC2s in cancer," Balachandran said. "The second take-home is we think for pancreas cancer specifically, IL33 could be a new potential immunotherapy for patients, and we are pretty excited about that."


Sarah LaCorte is an associate editor.