Study links survival outcomes in pancreatic cancer to immune cell placement in tumors

Study links survival outcomes in pancreatic cancer to immune cell placement in tumors

Johns Hopkins Medicine researchers have discovered that the organization of different types of immune cells in pancreatic tumors is linked to how well pancreatic cancer patients respond to treatment and how long they survive. The new findings, published Sept. 16 in Cancer Research, could eventually lead to new ways to treat pancreatic cancer, which has the highest mortality rate of any major cancer.

Mapping the location of specific immune cells associated with a tumor could be a new biomarker to predict patient survival. We hope that our findings will not only lead to a better fundamental understanding of cancer, but also have the potential to provide prognostic guidance to clinicians treating pancreatic cancer.”

Aleksander Popel, Ph.D., professor of biomedical engineering and director of the Systems Biology Laboratory, Johns Hopkins University School of Medicine and member of the Johns Hopkins Sidney Kimmel Cancer Center

The National Cancer Institute estimates that more than 62,000 Americans will be diagnosed with pancreatic cancer in 2022 and nearly 50,000 will die from the disease. On average, only about 10% of people with pancreatic cancer survive five years. It is difficult to predict which patients are most likely to respond to the few existing treatments; Researchers have long sought other tools — cells, molecules or genes — that stratify pancreatic cancer patients by survival.

In recent years, scientists studying many types of cancer have discovered the importance of the benign cells, molecules and blood vessels that surround tumors - called the tumor microenvironment. Part of this tumor microenvironment is immune cells; Some have the ability to attack a tumor for destruction, while others help the tumor evade the immune system.

In previous research on pancreatic cancer, researchers counted how many immune cells are present in the tumor microenvironment and found no connection to patients' outcomes, but Popel and Johns Hopkins graduate student Haoyang Mi hypothesized that the physical arrangement of immune cells may be more important than the total number.

In the new study, Popel, Mi and collaborators at Oregon Health & Science University used a method called multiplex immunohistochemistry to pinpoint the locations of 27 different immune molecules in surgically resected tumors from 45 people with pancreatic ductal adenocarcinoma — the most common form of pancreatic cancer. Patients were 52% women, had a median age of 63.5 years, and had all stages of cancer, with cancer spreading to at least four lymph nodes in 41% of participants.

The molecules found in various combinations on the surface of different immune cell types correspond to the relative positions of immune cell subtypes.

They then developed new computational algorithms to analyze how these cells differed in number, location and shape between patients who survived longer or shorter than the median survival time of 619 days.

“Using the computational approaches we developed, we analyzed not only the density of each cell type, but also how they interact with each other in the spatial architecture of the tumors,” says Mi, the first author of the new work.

The researchers discovered that among the 22 patients who survived for shorter than average periods (a median of 313 days), immune cells called IL-10+ myelomonocytes tended to be located near a cluster of granzyme B+ CD8+ T cells (or cytotoxic T lymphocytes). . Among the 23 patients who survived longer than average (median, 832 days), the same myelomonocytes were more clustered near another type of T cell known as PD-1+ CD4+ T cells (or activated helper T cells).

Given what is known about the function of each of these immune cells, the results make sense, says Mi. Each cell type acts like brakes on another. Cytotoxic T lymphocytes produce a toxin that can kill cancer cells, but - among short-term survivors - researchers suspect that nearby myelomonocytes block this ability. However, in long-term survivors, they suspect that the activated helper T cells switch off the myelomonocytes, which in turn allows the cytotoxic T lymphocytes to fight the cancer more effectively.

Further studies are needed to test these hypotheses about how the cells in the pancreatic tumor microenvironment interact, the researchers say, and to determine whether targeting either cell type could lead to new immunotherapies for pancreatic cancer. However, researchers hope that additional studies will confirm that the connection between the tumor microenvironment and survival can provide clinicians with prognostic information and potentially guide patients toward specific treatments or clinical trials.

Other researchers who contributed to the research include Elizabeth Jaffee of the Johns Hopkins Kimmel Cancer Center and Shamilene Sivagnanam, Courtney Betts, Shannon Liudahl and Lisa Coussens of Oregon Health & Science University.

The research was supported by the National Institutes of Health, the Knight Cancer Institute and the OHSU-Brenden-Colson Center for Pancreatic Care. https://www.hopkinsmedicine.org/“>Johns Hopkins

Source:

Johns Hopkins Medicine

Reference:

Mi, H., et al. (2022) Quantitative spatial profiling of immune populations in pancreatic ductal adenocarcinoma reveals tumor microenvironment heterogeneity and prognostic biomarkers. Cancer research. doi.org/10.1158/0008-5472.CAN-22-1190.

.