Seminar Series

Mutational tumor antigens appear to play a critical role in anti-tumor immune response. However, the identity of mutational antigens that elicit host-protective anti-tumor immunity is largely unknown. In human tumors, it is completely unknown at the moment; in mice, a handful of such neoepitopes have been defined over the decades using T cells, and recently, using DNA sequencing and bioinformatics. Bioinformatic pipelines that predict suitable neoepitopes abound, and vary in detail. Yet, they mostly hew to a consensus that suitable neoepitopes must have a high affinity for cognate MHC molecules (with an IC50 <500nM, preferably <50nM).

We present data that this view may be needlessly narrow. In two mouse models, where we have interrogated the mutations in the tumor genomes with a completely un-biased approach, and have examined several hundred potential neoepitopes, we observe that (a) ~ 1% of the total mutations encode true host-protective neoepitopes, (b) such neoepitopes bind MHC I molecules with predicted affinities far lower (worse) than IC50 values of 500nM, and (c) there is little correlation between the ability of a candidate neoepitope to elicit tumor rejection and CD8 T cells against the tumor as measured by ELISPOT assays. This is true even as the activity of the positive neoepitopes is clearly CD8-dependent. These observations suggest a need for re-consideration of the current consensus.​

Dr Pramod K. Srivastava academic profile

Hosted by Dr Sergio Quezada.

For further information please contact Veronica Dominguez.