CD5 blockade enhances ex vivo CD8⁺ T cell activation and tumour cell cytotoxicity

Abstract

CD5 is expressed on T cells and a subset of B cells (B1a). It can attenuate TCR signalling and impair 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 knockout mice show increased anti-tumour immunity: reducing CD5 on CTLs may be therapeutically beneficial to enhance the anti-tumour response. Here, we show that ex vivo administration of a function-blocking anti-CD5 MAb to primary mouse CTLs of both tumour-naïve mice and mice bearing murine 4T1 breast tumour homografts enhanced their capacity to respond to activation by treatment with anti-CD3/anti-CD28 MAbs or 4T1 tumour cell lysates. Furthermore, it enhanced TCR sig- nalling (ERK activation) and increased markers of T cell activation, including proliferation, CD69 levels, IFN-γ production, apoptosis and Fas receptor and Fas ligand levels. Finally, CD5 function-blocking MAb treatment enhanced the capacity of CD8 + T cells to kill 4T1mouse 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.Keywords: AICD r Anti-tumour immunity r CD5 r CD8 + T cell r Fas receptor Additional supporting information may be found online in the Supporting Information section at the end of the article. Faizah Alotaibi et al. Eur. J. Immunol. 2020. 50: 695-704 Abbreviations: AICD: activation-induce cell death · FasL: Fas ligand · FasR: Fas receptor · ICS: Intracellular cytokine staining · SRCR: scavenger receptor cysteine-rich · Treg: T regulatory

Reduced CD5 on CD8+ T Cells in Tumors but Not Lymphoid Organs Is Associated With Increased Activation and Effector Function

“…CD5 levels on both CD4 + T cells (Supplemental Figure 2A) and CD8 + T cells (Supplemental Figure 2B) were significantly higher in lymph nodes of mice harboring 4T1 tumors compared to naïve mice. Furthermore, as previously reported by us (25), CD5 levels on CD8 + T cell splenocytes were significantly increased after TCR/CD3 stimulation using ex vivo treatment with anti-CD3/anti-CD28 MAbs compared to non-stimulated CD8 + T splenocytes (25). Together, these results reveal that the presence of poorly immunogenic tumor homografts in mice leads to elevated CD5 on T cells in lymph nodes, similar to the increase in CD5 seen after ex vivo stimulation of the TCR/CD3 complex on CD8 + T cells.…”

“…The increased level of CD5 on T cells upon TCR/CD3 stimulation by monoclonal antibody treatment (25) or by exposure to poorly immunogenic 4T1 tumor antigen reported here suggests that CD5 level may be directly increased by that activation. To address how CD5 levels may be associated with T cell activation, a gating strategy was applied to determine the activation level of CD5 high T cells and CD5 low T cells based on the level of the T cell activation markers that are induced upon T cell activation, including CD69 (26), PD-1 (27), and CTLA-4 (28) (See Gating Strategy, Supplemental Figure 1).…”

CD95L and Anti-Tumor Immune Response: Current Understanding and New Evidence

“…In addition, experiments that directly alter TCR sensitivity by genetically or pharmacologically inhibiting CD95 signaling in the context of anti-tumor immunity and AICD have shown that these high-affinity T cells undergo CD95-mediated cell death and this cell death can be blocked with multiple inhibitors of CD95/CD95L signaling. 43 , 44 …”

Narcissistic T cells: reactivity to self makes a difference

“…Removal of the CD5-mediated inhibition could release the 'brake' which is normally imposed on strongly self-reactive T cells and unleash their full capacity during the immune responses. Consequently, the relatively self-reactive T cells would become even more self-reactive which could amplify their anti-tumor responses [77][78][79][80].…”