Targeting CD5 to enhance immune T cell activation and function in treatment of solid tumours

Faizah Alotaibi, The University of Western Ontario

Abstract

CD5 is a member of scavenger receptor cysteine-rich superfamily that is expressed primarily on T cells. It can attenuate T-cell receptor signaling and impair cytotoxic T lymphocyte (CTL) activation and is a therapeutic targetable tumour antigen expressed on leukemic T and B cells. However, the potential therapeutic effect of functionally blocking CD5 to increase T cell anti-tumour activity against tumours (including solid tumours) has not been explored. CD5^- solid tumours in CD5 knockout mice display increased in anti-tumour immunity. Hence, blocking CD5 function may have a potential therapeutic effect by enhancing CTL function. Here, I assessed CD5 levels in T cell subsets in different organs in mice bearing syngeneic 4T1 breast tumour homografts and determined the association between CD5 and increased CD69 and PD-1 (markers of T cell activation and exhaustion) by flow cytometry. I report that CD5 levels in T cells was higher in peripheral organs than in lymphocytes infiltrated into tumours, and that CD5^high T cells from peripheral organs exhibited higher levels of activation and exhaustion than CD5^low T cells from the same organs. Interestingly, among the population of tumour-infiltrated lymphocyte subtypes, CD8⁺ T cells with low CD5 were activated to a higher level than CD8⁺ T cells with high CD5, with concomitantly increased exhaustion markers. Thus, differential CD5 levels among T cells in tumours and lymphoid organs can be associated with different levels of T cell activation and exhaustion, suggesting that CD5 could be a therapeutic target for immunotherapeutic activation in cancer therapy. I then studied the effect on primary T cell effector function of targeting CD5 ex vivo using an anti-CD5 MAb. The result showed enhanced cytotoxic T cell capacity to respond to activation and enhanced the capacity of CD8⁺ T cells to kill 4T1-mouse tumour cells in an ex vivo assay. These data support the potential of blockade of CD5 function to enhance T cell-mediated anti-tumour immunity. Based on these results I tested anti-CD5 in vivo as a single agent and in combination with other drugs and found a significant increase in activation and effector function of T cells: an effect that resulted in decreased 4T1 tumour homograft growth in vivo. These data suggest potential use of anti-CD5 MAb to enhance immune activation to poorly immunogenic tumour antigens and reduce tumour growth.