From the AGA Journals

Forming specialized immune cell structures could combat pancreatic cancer

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Tertiary lymphoid structures step up to the plate

Pancreatic ductal adenocarcinoma (PDAC) is known for its remarkable resistance to immunotherapy. This observation is largely attributed to the microenvironment that surrounds PDAC due to its undisputed role in suppressing and excluding T cells – key mediators of productive cancer immune surveillance. This study by Delvecchio and colleagues now examines the formation and maturation of tertiary lymphoid structures (TLS) – highly organized immune cell communities – that can be found within murine and human PDAC tumors and correlate with a favorable prognosis after surgical resection in patients. Intriguingly, the authors show that intratumoral injection of lymphoid chemokines (CXCL13/CCL21) can trigger TLS formation in murine PDAC models and potentiate the activity of chemotherapy. Notably, in other solid cancers, the presence of mature TLS has been associated with response to immunotherapy raising the possibility that inciting TLS formation and maturation in PDAC may be a first step toward overcoming immune resistance in this lethal cancer. Still, much work is needed to understand mechanisms by which TLS influence PDAC biology and how to effectively deliver drugs to stimulate TLS beyond intratumoral injection which is less practical given the highly metastatic proclivity of PDAC. Nonetheless, TLS hold promise as a therapeutic target in PDAC and may even serve as a novel biomarker of treatment response.

Gregory L. Beatty, MD, PhD, is director of the Clinical and Translational Research Program for Pancreas Cancer at the Abramson Cancer Center of the University of Pennsylvania, Philadelphia, and associate professor in the department of medicine in the division of hematology/oncology at the University of Pennsylvania. He reports involvement with many pharmaceutical companies, as well as being the inventor of certain intellectual property and receiving royalties related to CAR T cells.



In a new study, researchers stimulated immune cells to assemble into tertiary lymphoid structures that improved the efficacy of chemotherapy in a preclinical model of pancreatic cancer.

Overall, the evidence generated by the study supports the notion that induction of tertiary lymphoid structures may potentiate chemotherapy’s antitumor activity, at least in a murine model of pancreatic ductal adenocarcinoma (PDAC). A more detailed understanding of tertiary lymphoid structure “kinetics and their induction, owing to multiple host and tumor factors, may help design personalized therapies harnessing the potential of immuno-oncology,” Francesca Delvecchio of Queen Mary University of London and colleagues wrote in Cellular and Molecular Gastroenterology and Hepatology.

While the immune system can play a role in combating cancer, a dense stroma surrounds pancreatic cancer cells, often blocking the ability of certain immune cells, such as T cells, from accessing the tumor. As shown by Young and colleagues, this causes immunotherapies to have very little success in the management of most pancreatic cancers, despite the efficacy of these therapies in other types of cancer.

In a proportion of patients with pancreatic cancer, clusters of immune cells can assemble tertiary lymphoid structures within the stroma that surrounds pancreatic cancer. These structures are associated with improved survival in PDAC. In the study, Mr. Delvecchio and colleagues sought to further elucidate the role of tertiary lymphoid structures in PDAC, particularly the structures’ antitumor potential.

The investigators analyzed donated tissue samples from patients to identify the presence of the structures within chemotherapy-naive human pancreatic cancer. Tertiary lymphoid structures were defined by the presence of tissue zones that were rich in T cells, B cells, and dendritic cells. Staining techniques were used to visualize the various cell types in the samples, revealing tertiary lymphoid structures in approximately 30% of tissue microarrays and 42% of the full section.

Multicolor immunofluorescence and immunohistochemistry were also used to characterize tertiary lymphoid structures in murine models of pancreatic cancer. Additionally, the investigators developed an orthotopic murine model to assess the development of the structures and their role in improving the therapeutic effects of chemotherapy. While tertiary lymphoid structures were not initially present in the preclinical murine model, B cells and T cells subsequently infiltrated into the tumor site following injection of lymphoid chemokines. These cells consequently assembled into the tertiary lymphoid structures.

In addition, the researchers combined chemotherapy gemcitabine with the intratumoral lymphoid chemokine and injected this combination treatment into orthotopic tumors. Following injection, the researchers observed “altered immune cell infiltration,” which facilitated the induction of tertiary lymphoid structures and potentiated antitumor activity of the chemotherapy. As a result, there was a significant reduction in the tumors, an effect the researchers did not find following the use of either treatment alone.

According to the investigators, the antitumor activity observed following induction of the tertiary lymphoid structures within the cancer is associated with B cell–mediated activation of dendritic cells, a key cell type involved in initiating an immune response.

Based on the findings, the researchers concluded that the combination of chemotherapy and lymphoid chemokines might be a viable strategy for promoting an antitumor immune response in pancreatic cancer. In turn, the researchers suggest this strategy may result in better clinical outcomes for patients with the disease. Additionally, the researchers wrote that mature tertiary lymphoid structures in PDAC prior to an immune treatment could “be used as a biomarker to define inclusion criteria of patients in immunotherapy protocols, with the aim to boost the ongoing antitumor immune response.”

The study relied on a mouse model and for this reason, it remains unclear at this time if the findings will be generalizable to humans. In the context of PDAC, the researchers wrote that further investigation and understanding of the formation of tertiary lymphoid structures may support the development of tailored treatments, including those that take advantage of the body’s immune system, to combat cancer and improve patient outcomes.

The researchers reported no conflicts of interest with the pharmaceutical industry. No funding was reported for the study.

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