Cancer neoepitopes viewed through negative selection and peripheral tolerance: a new path to cancer vaccines
Pramod K. Srivastava
Pramod K. Srivastava
Published March 1, 2024
Citation Information: J Clin Invest. 2024;134(5):e176740. https://doi.org/10.1172/JCI176740.
View: Text | PDF
Review

Cancer neoepitopes viewed through negative selection and peripheral tolerance: a new path to cancer vaccines

Abstract

A proportion of somatic mutations in tumors create neoepitopes that can prime T cell responses that target the MHC I–neoepitope complexes on tumor cells, mediating tumor control or rejection. Despite the compelling centrality of neoepitopes to cancer immunity, we know remarkably little about what constitutes a neoepitope that can mediate tumor control in vivo and what distinguishes such a neoepitope from the vast majority of similar candidate neoepitopes that are inefficacious in vivo. Studies in mice as well as clinical trials have begun to reveal the unexpected paradoxes in this area. Because cancer neoepitopes straddle that ambiguous ground between self and non-self, some rules that are fundamental to immunology of frankly non-self antigens, such as viral or model antigens, do not appear to apply to neoepitopes. Because neoepitopes are so similar to self-epitopes, with only small changes that render them non-self, immune response to them is regulated at least partially the way immune response to self is regulated. Therefore, neoepitopes are viewed and understood here through the clarifying lens of negative thymic selection. Here, the emergent questions in the biology and clinical applications of neoepitopes are discussed critically and a mechanistic and testable framework that explains the complexity and translational potential of these wonderful antigens is proposed.

Authors

Pramod K. Srivastava

×

Figure 4

A unifying hypothesis: the simplicity on the other side of complexity.

Options: View larger image (or click on image) Download as PowerPoint
A unifying hypothesis: the simplicity on the other side of complexity. (...
(A) The number of specific pMHC I complexes presented on the cell surface and pMHC-TCR affinity are the two major variables influencing TCR avidity. Other important variables, such as the level of expression of CD8α on T cells and the duration of the T cell–presenting cell interactions, are not shown. Adapted with permission from Journal of Immunology (120). (B) Other variables being the same, pMHC I affinity influences pMHC I–TCR avidity. If the pMHC I affinity is low and the pMHC-TCR affinity is low, the pMHC-TCR avidity is bound to be low. In case of a low pMHC affinity and a high pMHC-TCR affinity, the smaller number of pMHC molecules shall still drive the overall avidity to be biased toward the lower end. In case of a high pMHC affinity and a low pMHC-TCR affinity, the smaller number of pMHC molecules shall drive the overall avidity to be biased toward the lower end. If the pMHC I affinity is high and the pMHC-TCR affinity is also high, the pMHC-TCR avidity is bound to be high. Thus, in general, a low pMHC I affinity is most likely to drive the TCR avidity toward the lower end of the spectrum. (C) A metaphorical view of the universe of neoepitopes as an iceberg. The tip of the iceberg (the smaller component) harbors the high-affinity pMHC ligands while the submerged portion (the larger component) harbors the more abundant low-affinity pMHC ligands. The water level depicts the currently accepted threshold of productive pMHC affinity corresponding to an IC50 of about 100 nM.