Cancer vaccine enhanced non‐tumor‐reactive CD8 + T cells exhibit a distinct molecular program associated with ‘division arrest anergy’

Vaccination of cancer patients against tumor antigens can induce peptide‐specific but non‐tumor‐reactive (NTR) CD8 + T cells. We used NY‐ESO‐1 peptide‐specific CD8 + T cell clones to assess the molecular programs associated with lack of tumor‐reactivity. TCR sequences revealed that NTR and tumor‐reactive (TR) T cells are derived from distinct progenitors. NTR T cells are characterized by low avidity TCRs and lack of NY‐ESO‐1 tetramer binding. Most striking, NTR T cells are characterized by a molecular program associated with division arrest anergy with elevated expression of the inhibitory molecule p27 kip1 , high expression of CD25, CD7, and CD69 and modulated expression of coreceptors. NTR T cells also exhibit elevated expression of inhibitory molecules and reduced levels of transcription factors responsible for T cell activation. In vivo monitoring of the NTR CD8 + T cell clone using a TCR‐specific PCR revealed high prevalence of NTR T cell clones with even increased levels during vaccination. In vivo expansion of NTR T cells that can only be quantified by combining classical T cell cloning approaches with quantitative PCR adds another level of complexity to tumor host interaction. Certainly, these novel findings need to be considered when developing future adoptive T cell transfer approaches and cancer vaccines. Research support: Sofja Kovalevskaja Award (Alexander von Humboldt‐Foundation)