Researchers from the Spranger Lab have developed a new approach to cancer immunotherapy by examining antigen architectures and their impact on T cell response. This study aims to provide a blueprint for better cancer immunotherapies by uncovering new therapeutic strategies. The researchers created mouse models of lung cancer with well-defined expression patterns of cancer-associated antigens and analyzed how each antigen impacts T cell response. The key findings suggest that the widespread availability of an antigen across a tumor, what other antigens are expressed at the same time, and the relative binding strength and characteristics of antigens expressed by multiple cell populations in the tumor determine the immune response. This new approach may be effective for treating patients with tumors with high heterogeneity.
Publication Date: November 25, 2024
Immune Checkpoint Blockade (ICB) Therapies
Immune checkpoint blockade (ICB) therapies can be very effective against some cancers by helping the immune system recognize cancer cells that are masquerading as healthy cells. T cells are built to recognize specific pathogens or cancer cells, which they identify from the short fragments of proteins presented on their surface. These fragments are often referred to as antigens.
Heterogeneous Lung Tumor
A heterogeneous lung tumor, with different subpopulations of cells depicted in red and blue, is shown after treatment with a checkpoint blockade. T cells (white) attack some populations (blue) but not others (red), indicating that checkpoint blockade therapies might be ineffective for this tumor. A new vaccine from the Spranger Lab may help checkpoint blockades attack all cell populations and effectively treat the tumor.
RNA Vaccines and Antigen Selection
While RNA vaccines are being evaluated in clinical trials, current practice of antigen selection is based on the predicted stability of antigens on the surface of tumor cells. However, Spranger notes that it’s not so black-and-white, and even antigens that don’t make the numerical cut-off could be really valuable targets.
Therapeutic Strategies
Instead of just focusing on the numbers, we need to look inside the complex interplays between antigen hierarchies to uncover new and important therapeutic strategies. This study aims to provide a blueprint for better cancer immunotherapies by examining antigen architectures and their impact on T cell response.
Current Practice of Antigen Selection
While RNA vaccines are being evaluated in clinical trials, current practice of antigen selection is based on the predicted stability of antigens on the surface of tumor cells. However, this approach may not be effective for all types of cancer, as it does not take into account the complex interplay between different antigens and their expression patterns.
New Approach to Antigen Selection
The researchers took a new approach by examining antigen architectures and how they impact T cell response. They created mouse models of lung cancer with well-defined expression patterns of cancer-associated antigens and analyzed how each antigen impacts T cell response.
Key Findings
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The keys to immune response were found to be the widespread availability of an antigen across a tumor, what other antigens are expressed at the same time, and the relative binding strength and characteristics of antigens expressed by multiple cell populations in the tumor.
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In clonal tumors, mouse models were able to mount an immune response sufficient to control tumor growth when treated with ICB therapy, regardless of which combinations of weak or strong antigens were present.
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However, in subclonal tumors, competition rather than synergy was the rule, and tumors that lacked a strong antigen began to grow and developed the ability to evade immune attack and resist ICB therapy.
Designing an RNA-Based Vaccine
Incorporating these insights, the researchers designed an RNA-based vaccine to be delivered in combination with ICB treatment. The goal of this vaccine was to strengthen immune responses suppressed by antigen-driven dynamics.
Key Findings of the Vaccine Study
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Regardless of the binding affinity or other characteristics of the antigen targeted, the vaccine-ICB therapy combination was able to control tumors in mouse models.
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The widespread availability of an antigen across tumor cells determined the vaccine’s success, even if that antigen was associated with weak immune response.
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Analysis of clinical data across tumor types showed that the vaccine-ICB therapy combination may be an effective strategy for treating patients with tumors with high heterogeneity.
Future Work
In future work with the Irvine laboratory at the Scripps Research Institute, the Spranger laboratory will further optimize the vaccine with the aim of testing the therapy strategy in the clinic.
