Genetic Basis for Clinical Response to CTLA-4 Blockade

To the Editor: Snyder et al. (Dec.4 issue) 1 state that in patients with melanoma who clinically benefit from blockade of cytotoxic T-lymphocyte antigen 4 (CTLA-4), the tetrapeptide sequences in tumor neoantigens were identical to those in known antigenic peptides in pathogens.The authors probably correctly interpret that this coincidence reflects cross-reactivity between cancer neoepitopes and relevant epitopes from the microbial counterparts.However, another explanation is possible.It could be that there was a positive selection in the thymus for rearranged T-cell receptors (TCRs) that preferentially recognize pathogen-encoded and major histocompatibility complex (MHC)-presented antigenic epitopes.Such a feature could have been sculpted by evolution in TCR variable genes and HLA genes.More information about these interpretations could be gained by knowing the serologic status of the patients with respect to the putatively cross-reacting microbes.For instance, it would be very interesting to ascertain whether the serum samples from patient CR9306 were positive for anti-hepatitis D virus antibodies.Negative serologic status does not completely exclude previous subclinical contact with the infectious agent but would certainly argue against crossreactivity as an explanation for these observations.