Fresh research has illuminated the intricate molecular processes governing the responsiveness of specific cancers to immunotherapy. A recent study has unraveled the reasons behind the occasional ineffectiveness of immunotherapy in certain cancer types. This investigation, spearheaded by scientists at EMBL’s European Bioinformatics Institute (EMBL-EBI), Cold Spring Harbor Laboratory (CSHL), and the Massachusetts Institute of Technology (MIT), delves into the persistence of unresponsiveness to immune checkpoint blockade (ICB) therapy within some tumors. ICB therapy, a sanctioned approach that harnesses the patient’s immune system to combat and eliminate cancer cells, has revolutionized cancer treatment. Response rates range from 15% to 60%, yet the reasons for non-response in certain patients remain unclear. A comprehensive understanding of the underlying cellular processes could empower clinicians to predict which patients are more likely to respond and make informed treatment decisions.
ICB has been particularly effective in DNA mismatch repair deficient (MMRd) tumors. However, only about half of MMRd tumors respond to ICB, and even among responders, many experience unfortunate relapses. This study investigates the intricate mechanisms governing the response to ICB in patients with MMRd tumors. ICB operates by blocking immune checkpoints, signals that cancer cells exploit to evade detection by the immune system due to the high number of mutations present in these cells. These mutations can serve as signals that enable the immune system to identify and target the cancer. In the context of ICB, weaker mutation signals result in a diminished response to treatment because the immune system struggles to locate and recognize the cancer cells.
The results of this study, published in the journal Nature Genetics, spotlight the pivotal role played by intratumoral heterogeneity in this process. Intratumoral heterogeneity refers to a wide array of mutations scattered throughout the tumor, and it dampens the immune response, reducing the effectiveness of ICB treatment.
To illustrate this concept, Isidro Cortes-Ciriano, Research Group Leader at EMBL-EBI, offered an analogy: “One way to picture this is to imagine a crowd, where each person is holding a yellow flashlight. 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 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.”
Despite the remarkable efficacy of ICB in tumors with a high mutation rate, such as those with clonal neoantigens (identical mutations across all tumor cells), less than half of MMRd tumors display enduring responses to ICB. This study dissects the molecular mechanisms responsible for ICB resistance in MMRd tumors and reveals that intratumoral heterogeneity is a key factor diminishing the immune response and, consequently, the effectiveness of ICB treatment.
Peter Westcott, Assistant Professor at Cold Spring Harbor Laboratory and former Postdoctoral Researcher at MIT, remarked on the significance of this finding: “Our goal was to unravel the mystery of why certain tumors, which should respond to immunotherapy, do not. 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.”
These findings offer a pathway to identify patients more likely to benefit from ICB treatment, underscoring the necessity for personalized treatment strategies. The researchers used mouse models and clinical trial data from colon and gastric cancer patients to investigate and analyze tumor responses to ICB. The analysis revealed that colon and stomach tumors with a diluted mutational signal resulting from intratumoral heterogeneity exhibited reduced sensitivity to ICB treatment. This suggests that assessing the strength of the signal in individual tumors could help predict a patient’s response to ICB in clinical settings.
Isidro Cortes-Ciriano highlighted the importance of accessible clinical data, which was a challenge in this study, stating, “One of the major challenges of the study was getting access to clinical trial data. 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.”
Reference: “Mismatch repair deficiency is not sufficient to elicit tumor immunogenicity” by Peter M. K. Westcott, Francesc Muyas, Haley Hauck, Olivia C. Smith, Nathan J. Sacks, Zackery A. Ely, Alex M. Jaeger, William M. Rideout III, Daniel Zhang, Arjun Bhutkar, Mary C. Beytagh, David A. Canner, Grissel C. Jaramillo, Roderick T. Bronson, Santiago Naranjo, Abbey Jin, J. J. Patten, Amanda M. Cruz, Sean-Luc Shanahan, Isidro Cortes-Ciriano and Tyler Jacks, 14 September 2023, Nature Genetics. DOI: 10.1038/s41588-023-01499-4.