Uncovering the mechanisms underlying lack of response to immunotherapy 

New research improves understanding of the molecular mechanisms behind why some cancers respond to immunotherapy and others don't

Immune cells targeting a tumour
Uncovering the mechanisms underlying lack of response to immunotherapy. Credit: Karen Arnott/EMBL-EBI


    • Immune checkpoint blockade (ICB) is an approved immunotherapy for cancer treatment. However, ICB is only effective in some patients and it is still unclear why this is the case.
    • This study looks at the complex mechanisms underlying response to ICB in tumours with DNA mismatch repair deficiency (MMRd). Although tumours with MMRd have the highest response rate to ICB, still most patients do not respond.
    • The researchers use mouse models to demonstrate that inactivation of MMR is not enough to improve patient responsiveness to ICB.

A new study has shed light on why immunotherapy does not always work in certain types of cancer. Led by researchers at EMBL’s European Bioinformatics Institute (EMBL-EBI), Cold Spring Harbor Laboratory (CSHL), and the Massachusetts Institute of Technology (MIT), the work focuses on understanding why some tumours fail to respond to immune checkpoint blockade (ICB) therapy, an approved immunotherapy that harnesses the power of the patient’s immune system to target and destroy cancer cells. 

ICB has transformed the treatment landscape for cancer patients. Response rates range between 15% and 60%, but it is still unclear why some patients do not respond. Understanding what happens at the cellular level could help clinicians predict which patients are more likely to respond and guide treatment decisions. ICB is known to be most effective in DNA mismatch repair deficient (MMRd) tumours, but still only half of the MMRd tumours respond to ICB, and among responders, many will unfortunately relapse. This study looks at the complex mechanisms underlying response to ICB in patients with MMRd tumours.

What is DNA mismatch repair deficiency?

DNA mismatch repair (MMR) is a mechanism our bodies employ to recognise and repair DNA damage or mutations that occur during DNA replication. DNA mismatch repair deficiency means cells are not able to repair DNA mutations, which can result in cancer. MMRd tumours are more common in certain cancer types, for example, colon, stomach and uterine cancer.

ICB functions by obstructing an immune checkpoint – a signal exploited by cancer cells to stop the immune system from detecting the tumour through the high number of mutations found within these cancer cells. Such mutations can serve as cues that enable the immune system to identify and combat the tumour. In the context of ICB, weaker mutation signals lead to a diminished response to treatment because the immune system has a harder time finding and recognising the cancer cells.

The findings of this study, published in the journal Nature Genetics, highlight the pivotal role played in this process by intratumoral heterogeneity. 

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

What is intratumoral heterogeneity? 

Intratumoral heterogeneity is when many different mutations are found across the different cells that make up a tumour. This wide variety of mutations found across the tumour gives off a ‘diluted’ signal that the immune system can’t detect as easily as when the same mutations are found in all tumour cells.

“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 tumour, the stronger the signal and the more likely to trigger an immune response. However, if each person in the crowd has a different coloured 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.”

Understanding immunotherapy response 

ICB has shown remarkable efficacy in tumours with a high number of mutations, in particular, this applies to tumours with clonal neoantigens. Clonal neoantigens occur when identical mutations are present across all cells of a tumour. Despite this, less than half of MMRd tumours show long-lasting response to ICB, posing a significant challenge in optimising treatment. 

More about clonal neoantigens

These are unique, tumour-specific proteins that the immune system can potentially recognise as foreign. They arise from the genetic mutations that drive the growth and spread of cancer and neutral mutations that accumulate across the genome in the process. Because every cell in the tumour shares these clonal mutations, the presence of clonal neoantigens makes the tumour more visible and more likely to be targeted by the immune system, potentially enhancing the effectiveness of treatments like immunotherapies.

This study dissects the molecular mechanisms causing resistance to ICB in MMRd tumours and shows that intratumoral heterogeneity – a wide variety of mutations spread across the tumour – dampens the immune response, leading to diminished effectiveness of the ICB treatment. 

“Our goal was to unravel the mystery of why certain tumours, which should respond to immunotherapy, do not,” said Peter Westcott, Assistant Professor at Cold Spring Harbor Laboratory, former Postdoctoral Researcher at MIT. Regarding the tumours in their study, Westcott said, “There’s no question these tumours 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 personalised treatment strategies.”

From the investigation

In their investigation, the researchers used mouse models to demonstrate that inactivation of MMR is not enough to improve patient responsiveness to ICB.

“Our understanding of cancer is improving all the time, and this translates into better patient outcomes,” added Cortes-Ciriano. “Survival rates following a cancer diagnosis have significantly improved in the past twenty years, thanks to advanced research and clinical studies. We know that each patient’s cancer is different and will require a tailored approach. Personalised medicine must take into account new research that is helping us understand why cancer treatments work for some patients but not all.” 

Access to clinical data

The study used preclinical models, including mouse models and cell lines, as well as clinical trial data from colon and gastric cancer patients, to study and analyse tumour responses to ICB. 

Using clinical data, the researchers observed that colon and stomach tumours with a diluted mutational signal caused by intratumoral heterogeneity displayed reduced sensitivity to ICB treatment. This finding also suggests that identifying the level of signal strength in individual tumours could help predict a patient’s response to ICB in the clinic.

“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.”


This work was supported by EMBL core funding, by the Damon Runyon Cancer Research Foundation (Peter Westcott), and the National Cancer Institute, National Institutes of Health, United States (Tyler Jacks).

Source article(s)

Tags: bioinformatics, cancer, cancer immunotherapy, cortes-ciriano, embl-ebi, genomics, press release

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