The Immunogenicity and Anti-tumor Efficacy of a Rationally Designed Neoantigen Vaccine for B16F10 Mouse Melanoma.

Yan Zhang,Yuhua Wan,Huaman Cai,Li Deng,Zhibing Lin,Rongxiu Li

doi:10.3389/fimmu.2019.02472

Abstract

Tumor neoantigens are ideal targets for cancer immunotherapy as they are recognized by host immune system as foreigners and can elicit tumor-specific immune responses. However, existing strategies utilizing RNA or long peptides for the neoantigen vaccines render limited immune responses since only 20–30% of neoantigens predicted in silico to bind MHC I molecules are capable of eliciting immune responses with the majority of responding T cells are CD4+. Therefore, it warrants further exploration to enhance neoantigen-specific CD8+ T cells responses. Since neoantigens are naturally weak antigens, we asked whether foreign T help epitopes could enhance their immunogenicity. In present study, we chose 4 weak B16F10 neoantigens as vaccine targets, and fused them to the transmembrane domain of diphtheria toxin, namely DTT-neoAg. Strikingly, the vaccine elicited anti-tumor CD8+ T cells responses and enhanced tumor infiltration of both T cells and NK cells. Impressively, DTT-neoAg vaccine significantly deterred tumor growth with the inhibition rate reached 88% in the preventive model and 100% in the therapeutic model at low dose of tumor challenge. Furthermore, after second challenge with higher dose of tumor cells, 33.3% of the immunized mice remained tumor-free for 6 months in the therapeutic model. Because DTT is a non-toxic domain of diphtheria toxin, it may be not of great concern in terms of safety as a Th epitope provider. Thus, the fusion strategy employed by this study may become a feasible and powerful approach for development of personalized cancer vaccines.

Highlights

Genomic mutations altering signal transduction pathways that control cell proliferation or apoptosis can cause development of cancers [1]
Self-antigens shared by cancer patients have been used in the development of cancer vaccine, yet the clinical outcomes were disappointing [31]
One reason is that the self-antigens usually elicit low immune responses as they are subjected to central tolerance [15]

Summary

INTRODUCTION

Genomic mutations altering signal transduction pathways that control cell proliferation or apoptosis can cause development of cancers [1]. Only a limited fraction of non-synonymous mutations can naturally lead to activation of neoantigen specific CD4+ [16, 17] or CD8+ [18,19,20] T cells These cells are detectable within tumor-infiltrating lymphocytes or in peripheral blood. We show that the fusion antigens can elicit tumor-specific CD8+ cytotoxic T lymphocytes when formulated with CpG and Alum adjuvants, and enhance CD8+ T cells and NK cells’ infiltrating into tumor. This strategy would significantly expand the pool of candidate neoantigens, improve the effectiveness of the neoantigen vaccines and reduce the cost of patient-oriented vaccine design

MATERIALS AND METHODS

RESULT

DISCUSSION

Findings

ETHICS STATEMENT