Efforts in planning treatments and evaluating the prognosis for newly diagnosed breast cancer patients may have taken a leap forward thanks to a recent study carried out by a Johns Hopkins All Children’s research team in the Cancer & Blood Disorders Institute.

Their study, titled “Molecular Signature of Tumor-Associated High Endothelial Venules that can Predict Breast Cancer Survival,” was recently published in Cancer Immunology Research, a journal of the American Association for Cancer Research. This research is the latest in their quest for ways to help the natural immune system fight cancer through “adaptive immunity.”

Exploiting patients’ adaptive immunity, which is mediated by cancer-fighting T lymphocytes and B lymphocytes, is one of the most promising therapeutic strategies to treat many types of cancer. The hope and promise are that a boosted immune system can get to work more efficiently in its fight against cancer.

What are HEVs and Why Are They Important?

This most recent study explains how immune cells are “recruited” to tumors by blood vessels called “high endothelial venules,” or HEVs. HEVs transport the patient’s immune cells into a tumor’s interior to help in the fight against cancer.

“The immune system develops a defense against pathogens or malignant cells by recruiting disease-fighting white blood cells called ‘lymphocytes’ that circulate in the body,” explains Masanobu Komatsu, Ph.D., a senior scientist who led this study in the Johns Hopkins All Children’s Cancer & Blood Disorders Institute.

Komatsu compares immune system’s T cells and B cells to “soldiers” that get recruited into the battle against cancer and that HEVs are like “highways” for immune cells to help to get the “troops” to the tumors where they can fight cancer.

Malignant tumors, however, do not always develop functional HEVs.

“Tumors typically develop a lot of blood vessels, but many of these vessels are ‘defective,’” Komatsu says. “They are not capable of recruiting immune cells deeply into the interior of tumors. The tumors that have abundant HEVs to transport immune cells may only be seen in 20 to 30 percent of all cancer cases.”

Komatsu came to Johns Hopkins All Children’s in 2018, and he and his research team have been engaged in a number of research projects investigating HEVs. In another recent study, they investigated a RAS gene and its role in the immune system when the R-Ras gene is triggered by a small protein important in cell signaling called tumor necrosis factor (TNF). TNF also plays an important role in activating blood vessels to facilitate lymphocyte recruitment.

Finding the HEV Molecular Signature

Research by Komatsu and his colleagues in the current study was also aimed at determining which genes may be involved in immune cell recruitment and transport by HEVs. This meant looking for the HEV “molecular signature.”

“In many tumors, there are lymph node-like structures called tertiary lymphoid structures (TLS) that reside inside tumors or at the tumor periphery," explains Komatsu. "TLS are composed of clusters of accumulating immune cells that contain T cells, B cells and dendritic cells surrounding HEVs. It is the high density of TLS in tumors that correlates with a favorable prognosis for many types of cancers.”

For this study, the researchers compared breast cancer tissue samples in HEVs and non-HEV blood vessels to identify a “molecular signature” for the HEVs developed in tumors. At least four of the many genes they identified were found to be “upregulated” in HEVs, and confirmed by histological imaging.

“We found that tumor blood vessels that expressed several HEV-upregulated genes were associated with extensive infiltration of T and B cells,” the researchers wrote. “The high counts of those genes were associated with significant survival benefits for those with advanced breast cancer. The molecular signature of HEVs we identified will be useful to predict survival, and also provide a guide for cancer immunotherapies.”

Komatsu noted that Junko Sawada, D.V.M., Ph.D., of the Komatsu Lab is the lead author on the paper. Sawada is an instructor in the Johns Hopkins All Children’s Cancer & Blood Disorders Institute. Komatsu also stated that study co-author, Nobuyoshi Hiraoka, Ph.D., of Japan’s National Cancer Center pioneered research into HEVs.

The Future: Applying These Findings to Childhood Cancers

Many questions remain, and Komatsu identifies a “key question” about immunotherapy that involves finding ways to get more immune cells into the tumor by improving the HEVs’ gateway function. The big question is not only about learning how to enhance the HEV highway, but also about finding ways to improve the “combat-readiness” of immune cells that may be depleted or not in abundance.

He suggests that one answer might be found in newly developed “immune checkpoint blockade therapies,” which act by stimulating pathways to enhance the body's immune activity against tumors by blocking the immune-suppressing mechanism.

Komatsu references a factor called PD-1, a “checkpoint” protein on immune T cells. PD-1 normally acts as a type of “off switch” that helps keep the T cells from attacking healthy cells in the body when it attaches to PD-L1, a protein found on some normal regulatory cells as well as cancer cells. When PD-1 binds to PD-L1, it tells the T cells to cool off and stop fighting.

The researchers concluded that while the development of immune checkpoint blockers has revolutionized cancer treatment, and that newly developed drugs “have remarkable efficacy in some patients,” they also note that only a subset of patients respond to these therapies at present. Overcoming this limitation is an important challenge in cancer treatment today.

Their findings in this most recent study suggest that enhancing T cells and B cells, as well as enhancing the formation of HEVs to transport those cells into the interior of tumors, are good starting points for finding the cure for cancer.

While the study represents an advancement in treatment for breast cancer patients, the researchers also want to be able to translate this new knowledge to the treatment of certain pediatric cancers. According to Komatsu, they will be working with the pediatric oncology clinicians at Johns Hopkins All Children’s to do just that.