Goubard, A. | Search bioRxiv

bioRxiv2021

CISH targeting in NK cells activates natural cytotoxicity receptor signaling and reduce cell exhaustion to unsilence primary anti-tumor response

Cytokine inducible SH2-containing protein (CISH) is a natural killer (NK) cell negative regulator of cytokine signaling pathway. To further understand CISH functions in NK cells, we developed a conditional Cish-deficient mouse model in NK cells (Cishfl/flNcr1Ki/+). We detected no developmental or homeostatic difference in NK cells. However, global gene expression of Cishfl/flNcr1Ki/+ NK cells compared to Cish+/+Ncr1Ki/+ NK cells revealed upregulation of pathways and genes associated with NK cell cycling and activation. We show that CISH does not only regulate interleukin-15 (IL-15) signaling pathways but also natural cytotoxicity receptors (NCR) pathways. Indeed, CISH protein expression level increases upon NCR triggering. Primed Cishfl/flNcr1Ki/+ NK cells display increased activation upon NCR stimulation. Cishfl/flNcr1Ki/+ NK cells display lower activation thresholds and Cishfl/flNcr1Ki/+ mice are more resistant to tumor metastasis. Remarkably, we found that Cishfl/flNcr1Ki/+ mice were also more resistant to primary breast cancer growth in addition to superior control of spontaneous tumor metastasis. CISH deletion favors NK cell accumulation to the primary tumor, optimizes NK cell killing properties and decreases TIGIT immune checkpoint receptor expression, limiting NK cell exhaustion. Finally, we argue that specifically enhancing NK cell function is sufficient to boost anti-tumor response to both primary and secondary tumor models. Using CRISPRi, we then targeted CISH in human NK-92 or primary NK cells. According to the results in our mouse model, CISH deletion favors NCR signaling and anti-tumor functions in human NK cells. Our results validate CISH as an emerging therapeutic target to enhance NK cell immunotherapy.

immunology↗

bioRxiv2021

A syntenin-deficient microenvironment educates AML for aggressiveness

In acute myeloid leukemia (AML), the stromal microenvironment plays a prominent role in promoting tumor cell survival and progression. Although widely explored, the crosstalk between leukemic and stromal cells remains poorly understood. Syntenin, a multi-domain PDZ protein, controls both the trafficking and signaling of key molecules involved in intercellular communication. Therefore, we aimed to clarify the role of environmental syntenin in the progression of AML. By in vivo approaches in syngeneic mice, we demonstrate that a syntenin-deficient environment reprograms AML blasts to survive independently of the stroma. Up-regulation of EEF1A2 in the blasts controls this gain of cell survival. Furthermore, using ex vivo co-culture systems, we show that syntenin-deficient bone marrow stromal cells (BMSC) enhance the survival of different types of AML cells, including patient samples, and suffice to educate syngeneic AML, recapitulating micro-environmental effects observed in vivo. We establish that syntenin-deficiency causes an increase of eIF5A and autophagy-related factors in BMSC, and provide evidence that the inhibition of autophagy prevents syntenin-deficient BMSC to stimulate AML survival. Altogether, these findings indicate that host-syntenin in the BM microenvironment acts as a repressor of AML aggressiveness. Key points- A syntenin-deficient host reprograms AML blasts, enhancing total protein synthesis and cell survival pathways - Autophagy in the syntenin-deficient microenvironment is responsible for the gain of AML cell survival

cancer biology↗