Abstract
The specific recognition of T cell receptors (TCR) and peptides presented by human leukocyte antigens (pHLAs) is the core step for T cell triggering to execute anti-tumor activity. However, TCR assembly and soluble expression are challenging, which precludes the broad use of TCR in tumor therapy. Herein, we used heterodimeric Fc to assist in the correct assembly of TCRs to achieve the stable and soluble expression of several TCRs in mammalian cells, and the soluble TCRs enable us to yield novel bispecific T cell engagers (TCR/aCD3) through pairing them with an anti-CD3 antibody. The NY-ESO-1/LAGE-1 targeted TCR/aCD3 (NY-TCR/aCD3) that we generated can redirect naïve T cells to specific lysis antigen-positive tumor cells, but the potency of the NY-TCR/aCD3 was disappointing. Furthermore, we found that the activation of T cells by NY-TCR/aCD3 was mild and unabiding, and the activity of NY-TCR/aCD3 could be significantly improved when we replaced naïve T cells with pre-activated T cells. Therefore, we employed the robust T cell activation ability of staphylococcal enterotoxin C2 (SEC2) to optimize the activity of NY-TCR/aCD3. Moreover, we found that the secretions of SEC2-activated T cells can promote HLA-I expression and thus increase target levels, which may further contribute to improving the activity of NY-TCR/aCD3. Our study described novel strategies for soluble TCR expression, and the optimization of the generation and potency of TCR/aCD3 provided a representative for us to fully exploit TCRs for the precision targeting of cancers.
Highlights
In recent years, T cell-based immunotherapies, such as immune checkpoint inhibitors (ICIs) [1], adoptive cell therapy (ACT) [2,3], and cancer vaccines [4,5], have emerged as promising strategies for the treatment of cancer and have led to clinical remission in some patients
For both formats of NY-TCRmut, three bands appeared above the theoretical position on the reducing SDS-PAGE gel after purification, and the bands were restored to the proper size after deglycosylation, which likely reflected the partial glycan occupancy of the N-glycosylation sites (Figure 1B)
We used heterodimeric Fc to assist in the correct assembly of T cell receptors (TCR) to achieve the soluble expression of TCRs in mammalian cells, which allows for yielding novel TCR/aCD3 conveniently
Summary
T cell-based immunotherapies, such as immune checkpoint inhibitors (ICIs) [1], adoptive cell therapy (ACT) [2,3], and cancer vaccines [4,5], have emerged as promising strategies for the treatment of cancer and have led to clinical remission in some patients. The adverse effects of ICIs and CAR T therapies were caused by the deficient target specificity [3,6]. Specific peptide-based cancer vaccines have been proved to be feasible and safe, the mild effect of these cancer vaccines makes it difficult for these vaccines to meet clinical needs [9,10]. Novel immunotherapeutic strategies that simultaneously possess exquisite tumor specificity and high activity urgently need to be explored
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