The Potential and Challenges of Exploiting the Vast But Dynamic Neoepitope Landscape for Immunotherapy
Els M E Verdegaal1, Sjoerd H van der Burg1
1Experimental Cancer Immunology and Therapy Group, Leiden University Medical Center, Department of Medical Oncology, Leiden, Netherlands.
Abstract:
Somatic non-synonymous mutations in the DNA of tumor cells may result in the presentation of tumor-specific peptides to T cells. The recognition of these so-called neoepitopes now has been firmly linked to the clinical success of checkpoint blockade and adoptive T cell therapy. Following proof-of-principle studies in preclinical models there was a surge of strategies to identify and exploit genetically defined clonally expressed neoepitopes. These approaches assume that neoepitope availability remains stable during tumor progression but tumor genetics has taught us otherwise. Under the pressure of the immune system, neoepitope expression dynamically evolves rendering neoepitope specific T cells ineffective. This implies that the immunotherapeutic strategy applied should be flexible in order to cope with these changes and/or aiming at a broad range of epitopes to prevent the development of escape variants. Here, we will address the heterogeneous and dynamic expression of neoepitopes and describe our perspective and demonstrate possibilities how to further exploit the clinical potential of the neoepitope repertoire.
Insights
Tumor neoepitopes, recognized by T cells, are crucial for cancer immunotherapies. However, their expression changes during tumor growth, potentially limiting treatment effectiveness.
Area of Science:
- Immunology
- Oncology
- Genetics
Background:
- Somatic mutations in tumor DNA can create neoepitopes, which are recognized by T cells.
- Neoepitope recognition is linked to the success of cancer immunotherapies like checkpoint blockade and adoptive T cell therapy.
- Current strategies often assume stable neoepitope expression, which may not hold true in vivo.
Purpose of the Study:
- To address the dynamic and heterogeneous expression of neoepitopes during tumor progression.
- To explore flexible immunotherapeutic strategies that can adapt to evolving neoepitope landscapes.
- To highlight methods for exploiting the full potential of the neoepitope repertoire in cancer treatment.
Main Methods:
- Review of preclinical models and clinical data on neoepitope identification and T cell responses.
- Analysis of tumor genetic evolution under immune pressure.
- Discussion of strategies for dynamic neoepitope targeting and broad epitope repertoire exploitation.
Main Results:
- Neoepitope expression is not static and dynamically evolves under immune pressure.
- Immune system pressure can render T cells specific for certain neoepitopes ineffective.
- Tumor genetics and immune evasion mechanisms lead to changes in neoepitope availability.
Conclusions:
- Immunotherapeutic strategies must be flexible to accommodate dynamic neoepitope expression.
- Targeting a broad range of neoepitopes may prevent the emergence of immune escape variants.
- Further exploitation of the neoepitope repertoire is crucial for advancing cancer immunotherapy.
