Researchers at the La Jolla Institute for Immunology, led by Professor Stephen Schoenberger, Ph.D., are at the forefront of groundbreaking research aimed at harnessing the immune system’s capabilities to target cancer cells. Their focus lies in identifying a unique set of mutations called “neoantigens” that enable the immune system to distinguish between cancerous and normal cells.
Unlike traditional antibody-based cancer immunotherapies, which do not provide effective results for all patients, their work aims to bolster the immune response by enlisting the help of both CD4+ “helper” T cells and CD8+ “killer” T cells to combat formidable tumors. Professor Schoenberger, a member of the LJI Center for Cancer Immunotherapy, and his team have recently published two pivotal studies that highlight their innovative approach.
In a recent article in Nature Immunology, they underscore the critical role of CD4+ T cells in recognizing tumor cells. Their strategy hinges on a groundbreaking way to predict which neoantigens will trigger a robust CD4+ T cell response, facilitating the immune system’s ability to target tumor cells effectively. As Professor Schoenberger explains, tumor cells originate from normal cells in the body, making it challenging for the immune system to distinguish them as threats.
Unlike viruses, which often bear distinctive and non-human peptide sequences, tumor cells share most of their peptide sequences with normal cells, rendering them difficult to detect. However, with the guidance of CD4+ T cells, specialized immune cells called dendritic cells can capture these unique peptide sequences and present them to CD8+ T cells, effectively alerting the immune system. CD8+ T cells, in turn, execute the destruction of the tumor cells, but they require the cooperation of CD4+ T cells to do so efficiently.Â
To circumvent this challenge, Schoenberger and his colleague, LJI Professor Bjoern Peters, Ph.D., have developed computational tools that identify the genetic mutations and specific peptides serving as neoantigens to distinguish tumor cells from their normal counterparts. Their research, as outlined in the Nature Immunology study, demonstrates that CD4+ T cells recognizing a single target mutation can drive a diverse CD8+ T cell response, ultimately eradicating well-established tumors.
Additionally, the team discovered that the most effective responses occurred when the transferred CD4+ T cells were induced to develop into stem cell memory-like CD4+ T cells. These specialized T cells possess unique properties such as longevity and the ability to generate powerful effector cells. As the research transitions from the laboratory to clinical applications, these findings hold great promise for future clinical trials.
In a second study published in the Journal of Clinical Investigation, Professor Schoenberger’s team showcased a novel vaccine strategy designed to activate both CD4+ and CD8+ T cells, fostering their collaboration in eliminating large, aggressive tumors in a mouse model. For this study, Schoenberger collaborated with Joseph Dolina, Ph.D., a senior scientist at Pfizer Inc.
The team began by studying an aggressive squamous cell tumor with a low number of mutations, similar to many human cancers. They identified 270 mutations that set this tumor apart from normal cells and conducted in-depth investigations into 39 of these mutations. Remarkably, the researchers narrowed down the selection to five mutations recognized by the natural anti-tumor T cell response, with some targeted by CD4+ T cells and others by CD8+ T cells. Strikingly, only mutations targeted by both CD4+ and CD8+ T cells triggered protective or therapeutic responses against the tumor.
This discovery underscores the necessity for these neoantigens to be physically linked to mediate effective therapy, providing a path to make large tumors regress when the vaccine activates both CD4+ and CD8+ T cells through the same antigen-presenting cell. Looking ahead, Professor Schoenberger intends to collaborate with clinical colleagues at the UC San Diego Moores Cancer Center to investigate the effectiveness of this linked vaccine strategy in human patients.
This holds the potential to offer hope to individuals battling especially aggressive tumors. Furthermore, this research emphasizes the potential to significantly broaden the scope of patients who can benefit from checkpoint blockade immunotherapy when combined with personalized cancer vaccines. The novel approach of harnessing the natural synergy between CD4+ and CD8+ T cells presents a promising avenue in the fight against cancer.Â
