The researchers investigated how antigen expression patterns influence immune responses to tumors, focusing on factors such as how widely antigens are distributed across tumor cells, which other antigens are present, and the strength and characteristics of the antigens. Tumors with uniform antigen expression generally respond well to immune checkpoint blockade (ICB) therapies. However, tumors with heterogeneous antigen expression, where different subpopulations of cells present distinct antigens, present a challenge for immune response and therapy effectiveness.
In mouse models with clonal tumors (those with uniform antigen expression), ICB therapy effectively controlled tumor growth, regardless of whether the antigens were weak or strong. The study found that antigen strength influenced competition and synergy between T cell populations, mediated by cross-presenting dendritic cells in tumor-draining lymph nodes. When weak or strong antigens were paired together, competition between T cells reduced the immune response. In contrast, combining weak and strong antigens enhanced the overall T cell activity and response.
In subclonal tumors, which have diverse antigen signals across different cell populations, competition rather than synergy dominated, regardless of the antigen combinations. Initially, tumors with a subpopulation expressing a strong antigen responded to ICB therapy, but over time, areas lacking the strong antigen grew and developed resistance to immune attack and therapy. This highlights the complexity of immune dynamics in heterogeneous tumors and the difficulty in overcoming immune evasion.
To address this challenge, the researchers developed an RNA-based vaccine that, when combined with ICB therapy, boosted immune responses and controlled tumors in mouse models. The key to the vaccine’s success was not the strength of the antigen but its widespread expression across the tumor. Analysis of clinical data suggested that this combination therapy could be effective for patients with highly heterogeneous tumors, and the team plans further optimization and clinical testing in collaboration with the Scripps Research Institute.
About the Author of the Study – Dr. Stefani Spranger
Dr. Stefani Spranger is a distinguished researcher specializing in the interactions between cancer cells and immune cells, with a focus on understanding how these dynamics influence tumor progression and immune responses. She earned her PhD in 2011 from Ludwig-Maximilian University Munich in collaboration with Helmholtz-Zentrum Munich, where she also completed her MSc in Biology (2008) and BSc in Biology (2005).
Her research uses tumor mouse models designed to replicate human tumor dynamics, allowing her to study how immune cells respond to tumors over time and how cancer cells evade immune detection. A key focus of her work is the co-evolution of tumors and the immune system, exploring the relationship between tumor cells and immune cells such as T cells and dendritic cells in the tumor microenvironment. This research aims to develop strategies for improving the effectiveness of cancer immunotherapies, particularly immune checkpoint blockade (ICB) therapies.
Dr. Spranger’s work addresses challenges posed by tumor heterogeneity, where subpopulations of tumor cells express different antigens, affecting the immune system’s ability to recognize and eliminate them. Understanding this complexity is crucial for overcoming immune escape mechanisms and developing more targeted cancer treatments.
In recognition of her contributions to cancer immunology, Dr. Spranger was named a Forbeck Fellow in 2015, a prestigious award for exceptional young scientists in cancer research. Her ongoing work continues to impact the development of novel cancer therapies and deepen our understanding of the immune system’s role in tumor control.