New Study Unveils the Factors Behind Immunotherapy's Inconsistencies

A new research study has been conducted to understand the unresponsive behavior of tumors against immune checkpoint blockade (ICB) therapy, a recognized and approved treatment that utilizes the patient’s immune system to attack and eliminate cancer cells . The research was led by researchers at EMBL’s European Bioinformatics Institute (EMBL-EBI), Cold Spring Harbor Laboratory (CSHL), and the Massachusetts Institute of Technology (MIT). The study looks at the sophisticated mechanisms underlying response to ICB in patients with MMRd tumors.

The treatment landscape for cancer patients has completely been transformed by the ICB therapy. Even when the response rate ranges between 15%-60%, unresponsive patient behavior is still under doubt. A study set on the cellular level would be very helpful in comprehending the probability of patients who are more likely to respond and guiding treatment decisions, suggested researchers. The most effective therapy for DNA mismatch repair deficient (MMRd) tumors is known to be ICB but even after that only half of the MMRd tumors respond to ICB, and among several responders, there are some who relapse as well.

ICB functions by blocking an immune checkpoint – a signal which is used by the cancer cells to obstruct their detection by the immune system owing to the high mutation count within them. These mutations act as flags, helping the immune system spot and fight the tumor. With ICB, if these mutation signals are weak, the treatment response further weakens because it becomes more challenging for the immune system to detect and target the cancer cells.

This study also emphasizes the significant role of intratumoral heterogeneity in the process. The discoveries made by the researchers are also published in the journal Nature Genetics.

“This is an important body of work that provides new insights into the factors that control immune responses against cancer and why some tumors fail to respond to immune-stimulating therapies,” said Tyler Jacks, Professor at the Koch Institute at MIT.

“One way to picture this is to imagine a crowd, where each person is holding a yellow flashlight,” explained Isidro Cortes-Ciriano, Research Group Leader at EMBL-EBI. “If everyone turns on their flashlight, the beam of yellow light can be seen from far away. Similarly, the more cells with the same mutations in a tumor, the stronger the signal and the more likely it is to trigger an immune response. However, if each person in the crowd has a different colored flashlight, the light emanating from the crowd is less clear, and the signal becomes jumbled. Similarly, if cancer cells have different mutations, the signal is harder to make out and the immune system is not triggered, so ICB doesn’t work.”

This study exhibits how the presence of continuously mutating tumor cells makes it hard for the immune system to recognize and fight against the ICB treatment. The study also shows that deactivating MMR is just not enough to enhance patient responsiveness to ICB treatment. This was demonstrated by the researchers with the use of the mouse model.

“Our goal was to unravel the mystery of why certain tumors, which should respond to immunotherapy, do not,” said Peter Westcott, Assistant Professor at Cold Spring Harbor Laboratory, and former Postdoctoral Researcher at MIT. Regarding the tumors in their study, Westcott said, “There’s no question these tumors are MMRd, yet they’re not responding. That is a profoundly interesting negative result. By studying the mechanisms behind this resistance, we can pave the way for the development of more effective and personalized treatment strategies.”

Researchers used preclinical models, including mouse models and cell lines, as well as clinical trial data from colon and gastric cancer patients, to observe and examine tumor responses to ICB.

With the use of clinical data, the researchers observed that colon and stomach tumors with a diluted mutational signal caused by intratumoral heterogeneity exhibited reduced sensitivity to ICB treatment. Researchers also suggested that being able to identify the signal strength in individual tumors may also assist in the prediction of a patient’s response to ICB treatment.

“One of the major challenges of the study was getting access to clinical trial data,” explained Isidro Cortes-Ciriano. “This highlights once again how important it is for research data to be accessible via secure mechanisms so it can be reused to uncover new insights and improve our understanding of disease.”