Immune checkpoint blockade (ICB) therapies are proven to be effective for some cancers. They help the immune system recognize cancer cells that impersonate healthy cells. However, the effectiveness of these therapies depends on the distribution of cancer-associated antigens across the tumor.
Tumors with uniform antigen expression respond well to ICB therapy, while those with heterogeneous antigen distribution—where different subpopulations of tumor cells express different antigens—do not.
Most tumors exhibit this heterogeneous antigen expression, and its mechanisms remain poorly understood, hindering improvements in ICB therapy for these tumors.
In a new study, MIT scientists studied antigen expression patterns and associated T cell responses to determine why patients with heterogenous tumors respond poorly to ICB therapies. They identified specific antigen architectures to understand the immune system’s response to tumors.
More importantly, they built a therapeutic cancer vaccine that may improve tumor response to immune checkpoint blockade treatments. When combined with ICB therapies, this RNA-based vaccine has proven effective at controlling tumors in mouse models of lung cancer.
Boosting the power of immunotherapy in lung cancer
Stefani Spranger, associate professor of biology and MIT’s Koch Institute for Integrative Cancer Research member, said, “It’s not so black-and-white. Even antigens that don’t make the numerical cut-off could be valuable targets. Instead of focusing on the numbers, we must look inside the complex interplays between antigen hierarchies to uncover new and important therapeutic strategies.”
The team developed mouse models of lung cancer with different, well-defined patterns of cancer-associated antigen expression to study how these antigens affect T-cell responses. They created “clonal” tumors with uniform antigen expression and “subclonal” tumors that mimic the heterogeneous mix of tumor cells expressing various antigens.
They tested various antigen combinations with different binding affinities to MHC molecules. The researchers found that the key factors influencing the immune response were the extent to which an antigen was expressed across the tumor, the presence of other co-expressed antigens, and the binding strength and other characteristics of antigens across the tumor’s diverse cell populations.
T-cell treatment is improved by vaccination
The mouse models with clonal tumors successfully mounted an immune response that controlled tumor growth when treated with immune checkpoint blockade (ICB) therapy, regardless of the antigen combinations used. However, the researchers discovered that the relative strength of the antigens influenced the dynamics between T cell populations, which were mediated by cross-presenting dendritic cells in tumor-draining lymph nodes.
When two weak or two strong antigens were paired, competition between T cell populations reduced one of them. In contrast, pairing weak and strong antigens together enhanced the overall T cell response.
In subclonal tumors, where different cell populations express varying antigen signals, competition between T cell populations prevailed over synergy, regardless of the antigen combination. Initially, tumors with a subclonal population expressing a strong antigen responded well to immune checkpoint blockade (ICB) treatment. However, over time, tumor regions lacking the strong antigen began to grow and develop immune evasion mechanisms, leading to resistance to ICB therapy.
Building on these findings, the researchers designed an RNA-based vaccine to complement ICB treatment, aiming to counteract immune suppression caused by antigen-driven dynamics. Remarkably, the combination of the vaccine and ICB therapy successfully controlled tumors in mouse models, regardless of the antigen’s binding affinity or other characteristics.
The key factor for the vaccine’s success was the widespread expression of the antigen across tumor cells, even if that antigen was associated with a weak immune response.
Analysis of clinical data across various tumor types indicated that the vaccine-ICB therapy combination could be an effective treatment strategy for patients with highly heterogeneous tumors. Antigen expression patterns in patient tumors correlate with T cell synergy or competition observed in mouse models, influencing responsiveness to ICB therapy in cancer patients.
Moving forward, the research team, in collaboration with the Irvine laboratory at the Scripps Research Institute, plans to further optimize the vaccine and test this therapy strategy in clinical trials.
Journal Reference:
- Malte Roerden, Andrea Castro, Yufei Cui et al. Neoantigen architectures define immunogenicity and drive immune evasion of tumors with heterogenous neoantigen expression. The Journal for Immunotherapy of Cancer. DOI: 10.1136/jitc-2024-010249
