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SummaryMyc is a pleiotropic transcription factor involved in cancer, cell proliferation, and metabolism. Its regulation and function in Natural Killer (NK) cells, which are innate cytotoxic lymphocytes important to control viral infections and cancer, remain poorly defined. Here we show that mice deficient for Myc in NK cells presented a severe reduction in these lymphocytes. Myc was required for NK cell development and expansion in response to the key cytokine interleukin (IL)-15, which induced Myc through transcriptional and posttranslational mechanisms. Mechanistically, Myc ablationin vivolargely impacted NK cells’ ribosomagenesis, reducing their translation and expansion capacities. Similar results were obtained by inhibiting MYC in human NK cells. Impairing translation by pharmacological intervention phenocopied the consequences of deleting or blocking MYCin vitro. Notably, mice lacking Myc in NK cells exhibited defective anticancer immunity, which reflected their decreased numbers of mature NK cells exerting suboptimal cytotoxic functions. These results indicate that MYC is a central node in NK cells, connecting IL-15 to translational fitness, expansion, and anticancer immunity.

Anticancer T cells acquire a dysfunctional state characterized by poor effector function and expression of inhibitory receptors, such as PD-1. Blockade of PD-1 leads to T cell reinvigoration and is increasingly applied as an effective anticancer treatment. Recent work challenged the commonly held view that the phosphatase PTPN11 (known as SHP-2) is essential for PD-1 signaling in T cells, suggesting functional redundancy with the homologous phosphatase PTPN6 (SHP-1). Therefore, we investigated the effect of concomitant Ptpn6 and Ptpn11 deletion in T cells on their ability to mount antitumour responses. In vivo data show that neither sustained nor acute Ptpn6/11 deletion improves T cell-mediated tumor control. Sustained loss of Ptpn6/11 also impairs the therapeutic effects of anti-PD1 treatment. In vitro results show that Ptpn6/11-deleted CD8(+) T cells exhibit impaired expansion due to a survival defect and proteomics analyses reveal substantial alterations, including in apoptosis-related pathways. These data indicate that concomitant ablation of Ptpn6/11 in polyclonal T cells fails to improve their anticancer properties, implying that caution shall be taken when considering their inhibition for immunotherapeutic approaches.

MYC is a pleiotropic transcription factor involved in cancer, cell proliferation, and metabolism. Its regulation and function in NK cells, which are innate cytotoxic lymphocytes important to control viral infections and cancer, remain poorly defined. Here, we show that mice deficient for Myc in NK cells presented a severe reduction in these lymphocytes. Myc was required for NK cell development and expansion in response to the key cytokine IL-15, which induced Myc through transcriptional and posttranslational mechanisms. Mechanistically, Myc ablation in vivo largely impacted NK cells’ ribosomagenesis, reducing their translation and expansion capacities. Similar results were obtained by inhibiting MYC in human NK cells. Impairing translation by pharmacological intervention phenocopied the consequences of deleting or blocking MYC in vitro. Notably, mice lacking Myc in NK cells exhibited defective anticancer immunity, which reflected their decreased numbers of mature NK cells exerting suboptimal cytotoxic functions. These results indicate that MYC is a central node in NK cells, connecting IL-15 to translational fitness, expansion, and anticancer immunity.

After exposure to chronic inflammatory stimuli, the immune system can switch from a functional state where it acts to reestablish homeostasis to a dysfunctional state. In the context of cancer, T cells that become exposed to continuous stimulation eventually reach a state of exhaustion, characterized by poor effector function and expression of inhibitory receptors, such as PD-1. Although PD-1 signaling inhibition leads to T cell reinvigoration and has been applied as an effective treatment versus a wide range of tumors, the signaling pathway downstream of this receptor is still poorly understood. Recent work from others and us challenged the notion that the phosphatase shp-2 is essential for activation of the molecular cascade downstream PD-1 receptor engagement. The shp-2 homologue (shp-1) has also been associated with PD-1 signaling in T cells and functional redundancy between these phosphatases might occur downstream of this receptor. Therefore, we investigated the effect of shp-1 and the combination of both (shp-1/2) downstream of PD-1 by knocking out these phosphatases in T cells in a mouse model. In vivo results after tumor engraftment suggest that shp-1 as well as shp-1/2 deletion in T cells are not sufficient to ameliorate tumor control. Furthermore, ablation of shp-1 and shp-1/2 impair the beneficial effects of the anti-PD1 treatment. In fact, deletion of both phosphatases leads to decrease CD8+ T cell presence in the tumor microenvironment and in vitro results show that these cells have impaired survival. This data implies that elimination or inhibition of shp-1/2 is not a suitable strategy for effective immunotherapeutic approaches as well as highlights the importance of further elucidating the mechanisms behind this important inhibitory pathway. Citation Format: Pedro Ventura, Milica Gakovic, Berenice Fischer, Sarah Thomson, Hanif J Khameneh, Alessandro Zenobi, Giorgia Rota, Eric Vivier, Walter Birchmeier, Doreen Cantrell, Greta Guarda. Function of shp-1 and shp-2 phosphatases in T cell-mediated anti-tumor response [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P051.