Potentiating T Cell Tumor Targeting using a Combination of TCR/CAR with a Novel Siglec-based CCR

Abstract

Tumors may utilize different strategies to escape T-cells immunosurveillance. For example, the overexpression of checkpoint ligands (such as PDL1) is a well-known mechanism that dampens T-cell immune response. Additionally, it was found that cancer aberrant sialylation can, through the interaction with selected receptors such as those from the Siglec family may neutralize NK and T-cell function. Herein, we devised a novel receptor based on the extracellular portion of Siglec7 and the intracellular portion of CD28 or 41BB that can convert inhibitory signals into stimulatory ones when expressed in human T-cells. This costimulatory chimeric receptor (CCR) when co-expressed with a tumor
specific TCR or CAR facilitated higher cytokine secretion and activation profiles
following co-culture with tumor cells. Given the broad expression pattern of Siglec7 ligands on tumor cells, our data suggest this CCR may act as a general adjuvant to boost TCR or CAR T cell function. Overall, this work shed light on additional tumor evasion mechanisms mediated by sialylated residues and provide to an approach to improve engineered T-cell based cancer treatment.