Chemotherapy Changes the Immune Cell Landscape in Pancreatic Cancer

A new study demonstrates that chemotherapy impacts a patient’s immune system’s capacity to combat pancreatic cancer.

The investigation is being led by scientists at NYU Langone Health and its Perlmutter Cancer Center and focuses on the immune system, which has T cells made to combat external invaders like viruses. The system relies on “checkpoint” molecules like PD1 on T cell surfaces to instruct them to stop attacking when the proper signals are received, sparing normal cells.

Tumors are regarded as aberrant by the body as well, but cancer cells hijack checkpoints to suppress immune responses. One popular form of immunotherapy aims to disable checkpoints, rendering cancer cells once more “visible” to the immune system.

The study, which was published online on February 13 in the journal Nature Communications, examined more than 139,000 tumor cells taken from 27 patients with pancreatic ductal adenocarcinoma (PDAC), cancer that is difficult to diagnose and treat and in which only 12% of patients survive more than five years after diagnosis. A robust immune response to malignancies in the tissue surrounding them, say, researchers, is essential for reducing these pancreatic tumors.

A threefold drop in the synthesis of specific inhibitory checkpoint molecules was one of the new discoveries when 11 patients were compared to six others before and after chemotherapy. Current immunotherapies aimed at treating various cancers aim to block these “off” signals, notably PD1, but they have so far been ineffective against PDAC, according to studies.

The study also revealed that TIGIT, a second checkpoint, was the most prevalent inhibitory checkpoint molecule in PDAC and was 18 times more therapeutically targetable than PD1 before chemotherapy but only five times more therapeutically targetable after chemotherapy.

The results, according to the study’s authors, call for additional research into whether immunotherapies that target TIGIT instead of PD1 or programmed cell death protein 1, would be more successful in treating pancreatic ductal adenocarcinoma.

“Our study demonstrates how chemotherapy can have profound effects on the cellular landscape of the tumor microenvironment in pancreatic ductal adenocarcinoma,” said study co-senior investigator Aristotelis Tsirigos, Ph.D., a professor in the Departments of Medicine and Pathology at NYU Grossman School of Medicine, and a member of Perlmutter.

“Importantly, our results suggest that chemotherapy may promote resistance to subsequent immunotherapy in pancreatic ductal adenocarcinoma,” said study co-senior investigator Diane Simeone, MD, Laura and Isaac Perlmutter Professor of Surgery in the Department of Surgery at NYU Grossman School of Medicine.

“Further research is needed to determine if, as a result of this potential resistance, chemotherapy needs to be combined with immunotherapy at the start of treating this stubborn and often deadly form of cancer,” added Simeone, who is also a professor in the Department of Pathology at NYU Grossman, and director of the Pancreatic Cancer Center.

During chemotherapy, there were also changes in the quantity of other immune cells, how they interacted with one another, and reductions in other cancer-associated immune cells (such as fibroblasts and macrophages) that, if unregulated, would promote cancer growth. The exact treatment-related effects of these molecular alterations, the researchers warn, are still unknown.

Further research, according to Tsirigos, is being conducted to confirm the results in more cases. He adds that additional studies are required to see whether similarly thorough cell assessments of the tumor microenvironment performed quickly after diagnosis using a method termed scRNA-seq could aid in making future treatment choices.

During chemotherapy, there were also changes in the quantity of other immune cells, how they interacted with one another, and reductions in other cancer-associated immune cells (such as fibroblasts and macrophages) that, if unregulated, would promote cancer growth. The exact treatment-related effects of these molecular alterations, the researchers warn, are still unknown.

Further research, according to Tsirigos, is being conducted to confirm the results in more cases. He adds that additional studies are required to see whether similarly thorough cell assessments of the tumor microenvironment performed quickly after diagnosis using a method termed scRNA-seq could aid in making future treatment choices.

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