W182 - Evaluation of hhla2’s Dual Function on Innate and Adaptative Immunity

Virginie Huchet – CR2TI UMR1064; Mélanie Néel – CR2TI UMR1064; Manon Gricourt – CR2TI UMR1064; Gilles Blancho – CR2TI UMR1064; Simon Ville – CR2TI UMR1064; Fabienne Haspot – CR2TI UMR1064

Abstract Text: HHLA2 protein, a newly emerging B7 family’s member naturally expressed by epithelial cells of the gastrointestinal tract, has immunostimulatory and immunosuppressive functions on T and NK cells depending on the receptor engaged. Its overexpression, observed in many human tumours notably in PD-L1neg, suggests that HHLA2’s inhibitory function might result in tumour escape.

HHLA2’s activating receptor CD28H is express on 70% of circulating NK cells and on all naïve T cells. CD28H engagement increases T cell proliferation, cytokine production and NK cell cytotoxicity. The inhibitory effect of HHLA2 mediated by the KIR3DL3 receptor remains poorly understood. Importantly, KIR3DL3 and CD28H can simultaneously bind to HHLA2 at non-identical sites, with CD28H recognizing HHLA2-IgV1 domain while KIR3DL3 epitope remains undetermined.

To elucidate the consequences of HHLA2’s engagement on T and NK cells, we developed K562 cells expressing HHLA2. HHLA2 expression inhibits T and NK cell responses to K562 stimulation. Interestingly, we found that HHLA2 expression results in a rapid loss of membranous CD28H on T and NK cells. We then developed K562 cells expressing only HHLA2’s IgV1 portion. These cells only bind the activating receptor CD28H but not KIR3DL3. T or NK cells cultured with K562-V1 cells are then no longer inhibited and do not lose their CD28H expression. Whether we are describing a novel tumour escape mechanism tuned by HHLA2+ tumour cells through CD28H down-modulation on T and NK cells needs to be further clarified with tumour cells naturally expressing HHLA2.