Today’s cancer immunotherapies can be unpredictable. While they can be highly effective in some cases, in others they are not. This inconsistency has puzzled researchers.
Various theories have been proposed to explain this variability. It could be due to the number of mutations in a tumor, with more mutations potentially leading to better responses. It could also be influenced by the surrounding tissue environment, which can either support or hinder immune responses. However, none of these explanations have provided a definitive answer applicable to all cases.
Researchers from Memorial Sloan Kettering Cancer Center (MSK) and Baylor College of Medicine in Houston, Texas, have put forth a new theory.
“In order for immune cells to effectively target and kill tumor cells, they must arrange themselves in a specific spatial pattern,” explains Dr. Andrea Schietinger, a tumor immunologist at MSK’s Sloan Kettering Institute. “They need to form a triad.”
A triad consists of three distinct immune cells working together: a dendritic cell, a cytotoxic ‘killer’ T cell, and a helper T cell. While these cell types are commonly known in immunology, it was previously unknown that their physical presence together in tumors is crucial for mounting an effective immune response against cancer cells.
Their groundbreaking discovery, published in the journal Cancer Cell on July 8, 2024, has significant implications for therapy and could reshape the approach to administering immunotherapies.
Investigating the Failure of Elite Immune Responses
In their research, led by postdoctoral fellow Dr. Gabriel Espinosa-Carrasco, the team at MSK aimed to understand why adoptive T cell therapies, which involve expanding specific T cells in the lab and reintroducing them to the patient, sometimes fail despite logical expectations.
Dr. Schietinger questioned why perfectly engineered cytotoxic T cells, when infused into patients in large numbers, often fall short in eradicating cancer. This led her to consider the role of helper T cells in arming and activating cytotoxic T cells.
Empowering T Cells for Targeted Destruction
While conventional protocols activate cytotoxic T cells with helper T cell-derived chemicals for therapy, Dr. Schietinger hypothesized that helper T cells might be essential not only for activation but also for the actual killing function of cytotoxic T cells.
To test this hypothesis, they conducted experiments in mice with cancer, administering only cytotoxic T cells in contrast to including both cytotoxic and helper T cells. The results were striking: only when both T cell types were present did the tumors regress.
Dr. Schietinger emphasizes that having cytotoxic machinery alone is insufficient to execute the killing process; they require a ‘license’ from helper T cells. The formation of immune cell triads, observed in responsive mice, signaled the activation of cytotoxic T cells to take action against cancer cells.
Translating Discoveries to Human Applications
The team validated their findings in a study involving patients with pleural mesothelioma undergoing immune checkpoint blockade therapy at Baylor College of Medicine. Analysis of tissue samples revealed that responders had the crucial immune triads present in their tumors, while non-responders did not.
This evidence underscored the importance of immune cell triads in enhancing the anti-cancer immune response.
Implications for Clinical Practice
The discovery suggests that immune triads could serve as biomarkers for predicting immunotherapy responses, filling a current gap in biomarker availability.
Furthermore, the findings prompt a reconsideration of adoptive T cell therapy strategies, advocating for the inclusion of helper T cells alongside cytotoxic T cells for improved efficacy. It also raises implications for the design of cancer vaccines to bolster killer T cell responses.
Dr. Schietinger’s team is actively exploring these implications, developing tools to facilitate the formation of immune cell triads and collaborating on innovative cancer vaccine formulations to advance this research into clinical trials.
“Our research highlights the importance of spatial organization of immune cells over sheer numbers. Bringing these three cell types together is critical, and our focus is on developing therapeutics that achieve this coordination,” says Dr. Schietinger.
