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.

Figure 1. Model to explain the individually distinct antigenicities of cancers.

Identical normal cells are transformed by a driver mutation G, followed by multiple cell divisions (not shown) of each cell, resulting in random (and therefore individually distinct) mutations in two otherwise-identical cancer cells. A small proportion of these mutations are able to be presented by MHC molecules, resulting in individually distinct neoepitopes and immunopeptidomes. Adapted with permission from Advances in Cancer Research (6).

Figure 2. Dissonance between tumor control and CD8⁺ T cell response, as measured in vitro as well as pMHC I affinity.

Summary of the outcomes of an unbiased analysis of tumor control and CD8⁺ T cell responses elicited by 279 neoantigens isolated from a murine cancer cell line (62). The candidate neoepitopes that elicited tumor control in vivo did not elicit CD8⁺ T cell response, as measured by flow cytometry, even as their activity in vivo was CD8 dependent, as shown by depleting CD8⁺ T cells in vivo. The candidate neoepitopes that did elicit CD8⁺ T cell responses by flow cytometry did not elicit tumor control in vivo. Only 1 of 9 neoepitopes that mediated tumor control in vivo had a high affinity to MHC I (not shown).

Figure 3. A view of the key differences between TCR repertoires against non-self (viruses and model antigens) and self (cancer neoepitopes).

(A) Our standard understanding of positive and negative selection. (B) The TCR repertoire against non-self viral or model antigens is mostly untrimmed or unsculpted, because, with rare exceptions (as in ref. 119), these antigens have no self-counterparts. (C) In contrast, the TCR repertoire against cancer neoepitopes is profoundly trimmed or sculpted because of the self-evident similarity between cancer neoepitopes and self-antigens and the inherent cross-reactivity between the two. The TCR repertoire against cancer neoepitopes is thus proposed to be significantly narrower, qualitatively and quantitatively.

Figure 4. 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.