NTB-A RECEPTOR POTENTIATES ANTI-CANCER ACTIVITY OF CYTOTOXIC T LYMPHOCYTES AND REPRESENTS A POTENTIAL DRUGGABLE TARGET FOR CANCER IMMUNOTHERAPY

Cytotoxic CD8⁺ T lymphocytes are known to play a crucial rule in cancer immunotherapy. Their activation status stems from the net summary of co-stimulatory and co-inhibitory signals provided through various receptors such as CD28, 4-1BB, CTLA-4 and PD-1. Targeting these receptors has proven to be a potent therapeutic approach for improving the anti-tumor activity of effector lymphocytes. A clear interest therefore exists for identifying additional immune-receptors, capable of modulating anti-tumor T cell reactivity.

We have recently identified that the NTB-A receptor, a member of the SLAM family and a co-stimulatory homophilic receptor, has a role of modulating the function of CD8⁺ T cells[i]. The current study aims at investigating the functional impact of NTB-A engagement in CD8⁺ T cells. To this end, the extracellular soluble part of the NTB-A molecule (sNTB-A) was designed and produced. The effect of sNTB-A on T cell function was measured in melanoma patient-derived tumor infiltrating lymphocytes (TIL) and peripheral blood mononuclear cells (PBMCs) and it was explored in two experimental settings: (i) concurrent engagement of NTB-A and TCR in an antigen-independent manner; (ii) NTB-A engagement during T cell activation by cognate melanoma cells. Our main findings so far are: (1) sNTB-A augments melanoma-specific T cell reactivity, as measured by increased IFN-g production; (2) concomitant TCR and NTB-A engagement led CTL to dramatically up-regulate the expression of 4-1BB and, to a less extent, GITR co-stimulatory molecules. Finally, parallel engagement of NTB-A and 4-1BB during T cell stimulation by melanoma cells resulted in a synergistic effect and markedly improved anti-tumor CTL reactivity. Additional functions are currently under evaluation including the effect of sNTB-A on T cell survival and proliferation.