Researchers have discovered that the organization of different types of immune cells within pancreatic tumors may be associated with how well patients with pancreatic cancer respond to treatment, as well as how long they survive. This information could eventually lead to new ways of treating pancreatic cancer, according to findings published by Mi et al in Cancer Research.
“Mapping the location of certain immune cells associated with a tumor could be a new biomarker to predict patient survival,” said Aleksander S. Popel, PhD, Professor of Biomedical Engineering and Director of the Systems Biology Laboratory at the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. “We hope that our results will not only lead to a better fundamental understanding of cancer, but also [to] the potential to provide prognostic guidance to clinicians treating pancreatic cancer.”
The National Cancer Institute (NCI) estimated that by the end of 2022, more than 62,000 Americans will be diagnosed with pancreatic cancer and nearly 50,000 will die from the disease. On average, only about 10% of people with pancreatic cancer will survive for 5 years. Predicting which patients are most likely to respond to the few existing treatments is difficult; researchers have long been searching for more cells, molecules, or genes that may aid in stratifying patients with pancreatic cancer by survival.
In recent years, scientists studying many types of cancer have discovered the importance of the noncancerous cells, molecules, and blood vessels surrounding tumors, collectively called the tumor microenvironment. Part of this tumor microenvironment is comprised of immune cells; some have the ability to target a tumor for destruction, while others help the tumor evade the immune system.
In previous research on pancreatic cancer, researchers tallied up how many immune cells were present in the tumor microenvironment and found no association with patient outcomes, but Dr. Popel and colleagues hypothesized that the physical arrangement of immune cells might be more important than the total number.
In the new study, researchers used a method called multiplexed immunohistochemistry to pinpoint the locations of 27 different immune molecules in surgically resected tumors from 45 individuals with pancreatic ductal adenocarcinoma. The patients—52% of which were women aged 63.5 years on average—had all stages of cancer, with 41% of participants’ cancer having spread to at least four lymph nodes.
The molecules, found in different combinations on the surfaces of different immune cell types, corresponded to the relative locations of subtypes of immune cells.
Researchers then developed new computational algorithms to analyze how these cells varied in number, location, and shape between patients who survived longer or shorter than the median survival time of 619 days.
“With the computational approaches we developed, we analyzed not only the density of each cell type, but how they interacted with each other in the spatial architecture of the tumors,” said first study author Haoyang Mi, MD, a graduate student in the Department of Biomedical Engineering at the Johns Hopkins University School of Medicine.
The researchers discovered that, among the 22 patients who survived for a shorter period than the average time (a median survival of 313 days), immune cells called IL-10–positive myelomonocytes tended to be located close to a cluster of granzyme B–positive CD8–positive T cells (or cytotoxic T lymphocytes). Among the 23 patients who survived longer than average (a median survival of 832 days), the same myelomonocytes were more grouped near a different type of T cell, known as PD-1–positive CD4-positive T cells (or activated helper T cells).
In light of what is known about the function of each of these immune cells, Dr. Mi said, the results made sense. Each cell type acted like brakes on another. Cytotoxic T lymphocytes produced a toxin capable of killing cancer cells, but the researchers hypothesized that the nearby myelomonocytes blocked that ability in patients who survived shorter than the average. In patients who survived longer than the average, however, researchers proposed that the activated helper T cells switched off the myelomonocytes, which, in turn, let the cytotoxic T lymphocytes more effectively fight the cancer.
More studies are needed to verify the hypotheses surrounding how the cells are interacting in the pancreatic tumor microenvironment, the researchers said, as well as determine whether targeting any of the cell types could lead to new immunotherapies for pancreatic cancer. But the researchers expressed hope that additional studies will confirm that the tumor microenvironment’s association with survival can provide prognostic information to clinicians and potentially steer patients toward certain treatments or clinical trials.
Disclosure: This study was supported by the National Institutes of Health (NIH), the Knight Cancer Institute, and the Oregon Health & Sciences University Brenden-Colson Center for Pancreatic Care. For full disclosures of the study authors, visit aacrjournals.com.
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