Fully synthetic Mincle-dependent self-adjuvanting cancer vaccines elicit robust humoral and T cell-dependent immune responses and protect mice from tumor development.

Xiang Luo,Deying Yang,Zhongqiu Liu,Wenwei Li,Xiaoxiao Qi,Qinghai Lian,Liqing Chen,Lingqiang Gao,Guochao Liao,Renyu Zhang

doi:10.1039/d1sc05736g

Abstract

A new strategy based on a macrophage-inducible C-type lectin (Mincle) agonist was established to construct synthetic cancer vaccines. Using sialyl-Tn (STn) as a model antigen, four conjugates with the Mincle agonist as a built-in adjuvant were designed and synthesized through a facile and efficient method. All conjugates could induce BMDMs to produce inflammatory cytokines in a Mincle-dependent manner and were found to elicit robust humoral and T cell-dependent immune responses alone in mice. The corresponding antibodies could recognize, bind and exhibit complement-dependent cytotoxicity to STn-positive cancer cells, leading to tumor cell lysis. Moreover, all conjugates could effectively inhibit tumor growth and prolong the mice survival time in vivo, with therapeutic effects better than STn-CRM197/Al. Notably, compared to conventional glycoprotein conjugate vaccines, these fully synthetic conjugate vaccines do not cause “epitope suppression.” Mincle ligands thus hold great potential as a platform for the development of new vaccine carriers with self-adjuvanting properties for cancer treatment. Preliminary structure–activity relationship analysis shows that a vaccine containing one STn antigen carried by vizantin exhibits the best efficacy, providing support for further optimization and additional investigation into Mincle agonists as the carrier of self-adjuvanting cancer vaccines.

Highlights

Vaccination has become an effective strategy for cancer treatment due to its low side effects and high speci city.[1]
Preparation of glycoconjugates [1,2,3,4] In our synthetic design for target molecules [1,2,3,4] (Scheme 1), the key step was to selectively construct 6,60-diester trehalose derivatives containing one (7 and 8) or two (9 and 10) propargyl groups that could further couple with an STn antigen derivative equipped azide group by a click reaction, which has the advantages of superior stability, high yield and mild reaction conditions
Antisera induced by conjugate 5 exhibited strong reactivity to the CRM197 protein, and the CRM197speci c antibody titer was higher than that of the corresponding STn (101 725 vs. 82 747). These results demonstrate that CRM197 may inhibit the production of antibodies against the STn epitope, and conjugate [1,2,3,4] can avoid the in uence of the immunogenicity of the carrier molecules as much as possible

Summary

Introduction

Vaccination has become an effective strategy for cancer treatment due to its low side effects and high speci city.[1]. In the past few decades, many STn based vaccines have been designed, such as STn-KLH/QS21,4 STnKRN7000,31 and STn-CRM197/FA.[56] Among these, the conjugation vaccine of STn-KLH (Theratope®) was approved for clinical trials to treat colorectal and breast cancer It failed to display decreased disease progression or increased overall survival in phase III trials.[57] this therapeutic cancer vaccine failed, it provided valuable information and insight into the development of new anti-STn vaccines. (1) The STn antigen had an acceptable safety pro le for the development of antitumor vaccines; and (2) the utilization of an effective carrier to activate T cell-dependent immunity for the sufficient enhancement of STn immunogenicity may be possible to make the vaccine effective In this context, we were the rst to propose a new selfadjuvanting carbohydrate-based vaccine design using the Mincle agonist as a carrier molecule and built-in adjuvant. A monovalent cluster of cancer antigens may be more efficient than a single one;[58,59] conjugates containing

Results and discussion

Conclusions

A À low control A À low control