pDCs efficiently process synthetic long peptides to induce functional virus‐ and tumour‐specific T‐cell responses

Robust cell‐mediated immunity is required for immune control of tumours and protection from viral infections, with both CD4⁺ and CD8⁺ T cells playing a pivotal role. Synthetic long peptides (SLPs) represent an attractive way to induce such combined responses, as they contain both class I and class II epitopes. The ability of plasmacytoid dendritic cells (pDCs) to cross‐present SLPs has not yet been investigated; yet, pDCs play a critical role in shaping immune responses and have emerged as novel vectors for immunotherapy. Using overlapping 15‐mer peptide pools covering the entire sequence of CMVpp65 and MelA, representing a viral disease (cytomegalovirus, CMV) and a tumour (melanoma), respectively, we showed that human pDCs can effectively process SLPs. Our results demonstrated that pDCs potently cross‐present virus‐ and tumour‐derived SLPs and cross‐prime broad‐ranging, effective and long‐lived CD4⁺ and CD8⁺ T‐cell responses, triggering more efficient immune responses than short peptide loaded pDCs. This ability required intracellular processing by the proteasome and was enhanced by co‐exposure to TLR7/9‐L. Combining SLPs with pDCs represents a powerful immunotherapeutic strategy to elicit potent immune responses, which are required for clinical success in cancers and viral infections.