Immune checkpoint blockade (ICB) therapies have emerged as powerful treatments against certain cancers, enabling our immune system to identify and destroy cancer cells disguised as healthy cells.
T cells play a pivotal role in this process by recognizing specific pathogens or cancer cells, using fragments of proteins called antigens that are displayed on their surfaces. Because healthy cells lack these distinctive antigens, they remain unharmed.
However, even tumors that bear cancer-associated antigens can evade immune detection by expressing checkpoint proteins that effectively deactivate T cells. ICB therapies target these inhibitory proteins, reactivating T cells to attack cancer cells.
Recent research has revealed a crucial connection between the distribution of cancer-associated antigens and the effectiveness of checkpoint therapies. Tumors exhibiting uniform antigen signaling across most cells are more likely to respond well to treatment. In contrast, tumors with diverse antigens—often found in heterogeneous tumors—tend to show poor responses. This complexity in antigen profiles has made understanding tumor responses to ICB therapies challenging.
In a groundbreaking study, MIT researchers dissected antigen expression patterns alongside T cell responses, aiming to uncover the reasons behind the inadequate response of patients with heterogeneous tumors to ICB therapies. The researchers identified specific antigen arrangements that can significantly influence how the immune system reacts to tumors. They also developed an innovative RNA-based vaccine that, when paired with ICB therapies, proved effective in reducing tumor growth in mouse models of lung cancer.
Stefani Spranger, an associate professor of biology and a member of MIT’s Koch Institute for Integrative Cancer Research, led the study, which was recently published in the Journal for Immunotherapy of Cancer. The research team included prominent contributors such as Forest White and Darrell Irvine, a celebrated immunologist at Scripps Research Institute.
While RNA vaccines are currently under clinical investigation, the conventional method for antigen selection is primarily based on predicted antigen stability on the surface of tumor cells. Spranger emphasizes that “it’s not so black-and-white,” suggesting that even antigens that fall short numerically could represent valuable therapeutic targets. This insight encourages a shift from a purely numerical focus to a deeper exploration of the complex interactions among antigen hierarchies.
To understand the impact of different antigens on T cell responses, Spranger’s team created mouse models of lung cancer with well-defined patterns of cancer-associated antigen expression. They examined both “clonal” tumors, which have uniform antigen presentation across cells, and “subclonal” tumors, representing a mix of various antigen-expressing cell populations. Different combinations of antigens with varying affinities to major histocompatibility complex (MHC) were tested in each model.
The findings revealed that the extent to which an antigen is expressed throughout a tumor, the presence of other simultaneously expressed antigens, and the relative binding strengths influenced T cell responses significantly. In clonal tumors, an effective immune response was observed with ICB treatment irrespective of the strength of the antigens involved. Conversely, subclonal tumors displayed competitive dynamics among T cell populations, with immune responses varying based on the antigens present.
In these subclonal tumors, initially controlled under ICB treatment due to a strong antigen presence, resistance often developed over time as weaker antigen-containing tumor cells proliferated and escaped immune attack.
Armed with these insights, the researchers crafted an RNA-based vaccine to be administered alongside ICB treatment, aimed at enhancing immune responses diminished by antigen-induced dynamics. They discovered that irrespective of the targeted antigen’s binding affinity, the combination of the vaccine with ICB therapy effectively managed tumor growth in mouse models. The crucial factor determining the vaccine’s success was the widespread presence of an antigen, even if it was associated with a weak immune response.
Analysis of clinical data across various tumor types indicates that this vaccine-ICB therapy combination could represent a viable treatment approach for patients with highly heterogeneous tumors. The correlation between antigen distributions in patient tumors and T cell dynamics observed in mouse models underscores the potential for enhanced responsiveness to ICB therapy. Looking ahead, Spranger’s laboratory plans to collaborate with Irvine’s lab at Scripps Research Institute to further refine the vaccine and explore its clinical applications.
Photo credit & article inspired by: Massachusetts Institute of Technology
