Cancer comprises a multitude of different diseases, and every patient reacts differently to frequently used therapeutic approaches, such as radiation and chemotherapy. In the late 19th and the early 20th century, the first attempts in the Western world were made to infect patients with weakened bacteria or viruses to activate their natural defense mechanism, aka the immune system. The results were not overwhelming, but scientists still believed that triggering the immune system might be a successful strategy to fight cancer and kept engaging in basic research into immunity regulation.

Remarkable scientific progress has been made since then, but that has only rarely led to generally applicable cancer treatments. However, a change is on the horizon… "When it works, immunotherapy is truly amazing," says Diether Lambrechts, Group Leader at the VIB-KU Leuven Center for Cancer Biology.

In 2018, James P. Allison and Tasuku Honjo jointly received the Nobel Prize in Physiology or Medicine. Allison and Honjo each examined a different protein and found that both work as a "brake" on the immune system. Releasing that brake and unleashing our immune cells to attack tumors became known as immune-checkpoint blockade (ICB), the mechanism behind a type of immunotherapy called immune-checkpoint blockage therapy.

Over the past few years, the potential of ICB therapy has been investigated through hundreds of clinical studies in multiple cancer types. In many cases, the clinical trials showed encouraging positive effects. However, the results were also extremely variable and unpredictable, while resistance, relapse, and side-effects were common.

To accelerate progress in this emerging field of cancer treatment, VIB started the Pointillism research track within the Grand Challenges Program in 2018. "Immunotherapy is a real gamechanger," states Diether Lambrechts, who's in charge of the track. "For some people, it means the difference between life and death, as simple as that. That's why we want to gain as many insights as possible, as soon as possible. Our main goal is being able to predict, before immunotherapy starts, which patients will, and which won't respond to the therapy. For those who won't, we want to use that information to develop different treatments that can extend their lifespan in a qualitative way."

In the Pointillism project, immunotherapy trials have been selected in four different cancer types, to assemble a comprehensive collection of pre- and on-treatment biopsies from patients. Lambrechts: "Since breast cancer is the most common cancer type we're investigating, that particular trial delivered the first results. In collaboration with the Multidisciplinary Breast Center of UZ Leuven, we used single-cell technology to study the tumor microenvironment of 40 early breast cancer patients treated with immunotherapy. This is the first time such a large cohort of breast cancer patients has been analyzed on the single-cell level."

"The results show clear differences between patients that are predicted to respond to the therapy, so-called responders, and the non-responders for whom we predict the therapy will not work. The clear but subtle differences wouldn't be noticed with other approaches. Studying the differences between both groups allowed us to define a surrogate marker for response based on specific characteristics of the tumor and its micro-environment. This shows that our fine-grained single-cell maps of the changes in the tumor microenvironment during treatment yield results."