Abstract
Personalized cancer vaccines targeting neoantigens arising from somatic missense mutations are currently being evaluated for the treatment of various cancers due to their potential to elicit a multivalent, tumor-specific immune response. Several cancers express a low number of neoantigens; in these cases, ensuring the immunotherapeutic potential of each neoantigen-derived epitope (neoepitope) is crucial. In this study, we discovered that therapeutic vaccines targeting immunodominant major histocompatibility complex (MHC) I-restricted neoepitopes require a conjoined helper epitope in order to induce a cytotoxic, neoepitope-specific CD8+ T-cell response. Furthermore, we show that the universally immunogenic helper epitope P30 can fulfill this requisite helper function. Remarkably, conjoined P30 was able to unveil immune and antitumor responses to subdominant MHC I-restricted neoepitopes that were, otherwise, poorly immunogenic. Together, these data provide key insights into effective neoantigen vaccine design and demonstrate a translatable strategy using a universal helper epitope that can improve therapeutic responses to MHC I-restricted neoepitopes.
Highlights
T-cell-based immunotherapy is currently being explored for the treatment of various cancers, considering the molecular-guided precision and high cytotoxic potential of T cells
ELISpot analysis revealed that the Odc129mer synthetic long peptide (SLP) vaccine, but not the Odc1MHC I peptide vaccine, elicited a robust IFNγ+ response towards the minimal Odc[1] major histocompatibility complex (MHC) I-restricted neoepitope, indicative of an Odc1MHC I-specific CD8+ T-cell response[8], and elimination of these cells through CD8+ depletions at the effector phase abrogated the antitumor effect (Fig. 1b, c), suggesting that the antitumor effects of the Odc129mer SLP vaccine are mediated by CD8+ Odc1MHC I-specific cytotoxic lymphocytes (CTLs)
Peptide length alone can facilitate enhanced CTL responses[9], some SLP-mediated CTL responses are enhanced by an endogenous MHC II-restricted epitope[10]
Summary
T-cell-based immunotherapy is currently being explored for the treatment of various cancers, considering the molecular-guided precision and high cytotoxic potential of T cells. The advent of next-generation sequencing has enabled a comprehensive assessment of antigens expressed by a given tumor, offering numerous immunotherapeutic targets for vaccine strategies Among these approaches, vaccines targeting neoantigens that arise from tumor-specific somatic missense mutations have garnered significant interest in the clinic[1,2,3,4,5,6] owing to their ability to induce a multivalent, tumor-focused immune response. Vaccines targeting neoantigens that arise from tumor-specific somatic missense mutations have garnered significant interest in the clinic[1,2,3,4,5,6] owing to their ability to induce a multivalent, tumor-focused immune response Some tumor types, such as newly diagnosed glioblastoma multiforme (GBM), possess an intrinsically low somatic mutation load[7], providing only a limited number of potential immunotherapeutic targets for neoantigen vaccines. Neoepitopes and provide encouraging insights for clinical neoantigen vaccine design, especially for tumors exhibiting a low mutation load
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