By Rachel Tompa, Ph.D. / Allen Institute

A new study sifting through biopsies from 22 Hodgkin lymphoma patients, cell by single cell, has identified tricks this cancer uses to hide itself from the immune system — and a potential new avenue for targeted treatments.

These tricks, it turns out, have more to do with lymphoma’s surroundings than the cancerous cells themselves.

It may come as a surprise to learn that most cancers are not just cancer itself, but a collection of tumor cells and the body’s healthy cells, co-opted by the cancer into a dysfunctional milieu of tumor growth and immune-system suppression. It’s like a toxic work environment, only far more deadly.

Cancer’s supporting cast of healthy cells is known as the “tumor microenvironment,” and, for almost every kind of cancer, it turns out to be incredibly important in the context of treatment and patient outcome.

Nowhere is this phenomenon more obvious than in Hodgkin lymphoma, a blood cancer whose tumors are made up of a whopping 99% immune cells and just 1% actual cancerous cells. But all those immune cells are not hanging around because they’re fighting the cancer.

“It turns out the malignant cells make other cells do their dirty work for them, so they have a cozy environment where they can thrive,” said Christian Steidl, M.D., a lymphoma researcher at BC Cancer and the University of British Columbia who led the study profiling this unique microenvironment, which was published in the journal Cancer Discovery last month.

Breaking down lymphoma’s walls

Steidl, who is also an Allen Distinguished Investigator, and his colleagues found that Hodgkin lymphoma tumors bear a type of immune cell that are not or are only rarely found in healthy people and patients with other kinds of lymphoma. These immune cells, a type of T cell, contain a unique protein that indicates a specific mode of action — instead of doing their job fighting foreign invaders or cancer cells, the T cells have been molecularly altered to shut down their normal functions and also to instruct other immune cells to do the same.

The research team also found that these T cells arrange themselves around cancer cells, like tiny castle walls that physically shield the lymphoma cells from the rest of the immune system. In other experiments, the researchers showed that the cancerous cells trigger this T-cell transformation by releasing certain molecular instructions into their surroundings.

Drugs already exist that target that unique T-cell protein, which is known as LAG3, and clinical trials are underway testing these drugs for patients with Hodgkin lymphoma and other related lymphomas. Immunotherapy, a class of treatments that alter or boost a patient’s own immune system to recognize and kill their tumors, is showing promise for certain cancers, including Hodgkin lymphoma, but not all patients respond. That’s likely because every patient’s tumor and tumor microenvironment is slightly different — meaning detailed molecular profiles like the current study can lay the groundwork to better tailor therapies for each patient, Steidl said.

Not every patient in the study had high levels of T cells with LAG3, so it’s possible different immunotherapies would work better on patients with high or low levels of these cells. The team is now studying Hodgkin lymphoma patients who are enrolled in clinical trials to understand whether these newly discovered T cells correlate with treatment response and patient outcome.

Single-cell advances

The study, which was supported in part by Steidl’s award through The Paul G. Allen Frontiers Group, a division of the Allen Institute, could not have been done just ten years ago, the researcher said. Technologies allowing scientists to capture the entire suite of switched-on genes in an individual cell, collectively known as single-cell transcriptomics, are enabling insights not previously possible.

“To fully understand the ecosystem of Hodgkin lymphoma and the relationships between all these cells, we need to look at the single-cell level,” Steidl said. “And from a clinical point of view, we have to understand this ecosystem to find and tailor the best therapy for the patients’ needs.”