Some cancers respond well to immuno-checkpoint blockade therapy (ICB). These therapies help the immune system to recognize cancerous cells masquerading as healthy cells. The effectiveness of these treatments depends, however, on the distribution and density of antigens associated with cancer across tumors.
ICB treatment is effective for tumors that express uniform antigens, but not those that have heterogeneous distribution of antigens (where subpopulations within the cancer cells are expressing different antigens).
The mechanisms of this antigen heterogeneity are still poorly understood and hinder the development of ICB therapies for tumors.
In a recent study, MIT researchers studied the antigen expression pattern and T-cell responses associated with it to understand why patients who have heterogeneous tumors do not respond well to ICB treatments. The researchers identified antigen architectures in order to better understand how the immune system responds to tumors.
They also developed a cancer therapeutic vaccine which may enhance tumor response to treatments involving immune checkpoint blocking. This RNA-based cancer vaccine, when combined with ICB treatments, has shown to be effective in controlling lung tumors.
Immunotherapy for lung cancer: Increasing its power
Stefani Spranger is an associate professor at MIT and a member of the Koch Institute for Integrative Cancer Research. It’s not as black and white as you might think. Antigens which do not meet the cut-off number could still be useful targets. We must instead focus on the interplays of antigen hierarchy to discover new therapeutic strategies.
To study the effects of antigens on T-cells, the team created mouse models with well-defined antigen patterns. The team created clonal tumors, which had uniform antigen expression. They also made “subclonal tumors”, which mimicked the heterogeneous mixture of tumor cells that express various antigens.
The researchers tested different antigen combinations that had different binding affinity to MHC molecules. Researchers found the most important factors that influence the immune response are the amount of an antigen expressed in the tumor and its diverse cell population, as well as the co-expression of other antigens.
Vaccination is an effective way to treat T-cells
The immune responses mounted by the mouse models that had clonal tumours were effective in controlling tumor growth, regardless of antigen combinations. The researchers found that antigen strength influenced T-cell dynamics, and this was mediated through cross-presenting Dendritic Cells in lymph nodes draining tumors.
Competition between two T-cell populations was reduced when two antigens, either weak or strong, were paired. Comparatively, pairing strong and weak antigens increased the T-cell response.
In subclonal tumours where the different T-cell populations expressed varying antigens, competition prevailed, no matter what antigen combinations were used. Initially tumors with a population of subclones expressing a powerful antigen were well-responded to the immune checkpoint blocking (ICB). Over time, however, the tumor areas lacking the antigen began growing and developing immune evasion strategies, leading to ICB resistance.
Based on their findings, researchers developed an RNA vaccine as a complement to ICB therapy, aiming at countering immune suppression due to antigen-driven dynamic. The combination of vaccines and ICB treatment successfully controlled tumors, regardless of antigen binding affinity, or any other characteristic.
It was important that the antigen spread across the tumor cells even though it was only associated with a mild immune response.
The analysis of data from patients across a wide range of tumor types revealed that combining ICB with vaccine therapy could provide a highly effective strategy to treat heterogeneous cancers. The antigen expression pattern in tumors of cancer patients correlates with the T cell competition or synergy observed in mice models. This influences response to ICB treatment in cancer patient.
The research team plans to continue optimizing the vaccine in conjunction with Scripps Research Institute’s Irvine Laboratory and then test the therapy in clinical trials.
Journal Reference
- Malte Roerden, Andrea Castro, Yufei Cui et al. Neoantigen structures define immunogenicity, and they drive immune evasion in tumors that express heterogeneous neoantigens. The Journal for Immunotherapy of Cancer. DOI: 10.1136/jitc-2024-010249
