SLFN11 can sensitize tumor cells towards IFN-γ-mediated T cell killing

Abstract

Experimental and clinical observations have highlighted the role of cytotoxic T cells in human tumor control. However, the parameters that control tumor cell sensitivity to T cell attack remain incompletely understood. To identify modulators of tumor cell sensitivity to T cell effector mechanisms, we performed a whole genome haploid screen in HAP1 cells. Selection of tumor cells by exposure to tumor-specific T cells identified components of the interferon-γ (IFN-γ) receptor (IFNGR) signaling pathway, and tumor cell killing by cytotoxic T cells was shown to be in large part mediated by the pro-apoptotic effects of IFN-γ. Notably, we identified schlafen 11 (SLFN11), a known modulator of DNA damage toxicity, as a regulator of tumor cell sensitivity to T cell-secreted IFN-γ. SLFN11 does not influence IFNGR signaling, but couples IFNGR signaling to the induction of the DNA damage response (DDR) in a context dependent fashion. In line with this role of SLFN11, loss of SLFN11 can reduce IFN-γ mediated toxicity. Collectively, our data indicate that SLFN11 can couple IFN-γ exposure of tumor cells to DDR and cellular apoptosis. Future work should reveal the mechanistic basis for the link between IFNGR signaling and DNA damage response, and identify tumor cell types in which SLFN11 contributes to the anti-tumor activity of T cells.

Tumor Heterogeneity Underlies Differential Cisplatin Sensitivity in Mouse Models of Small-Cell Lung Cancer

“…In addition, chemotherapy resistance mechanisms associated with the frequently observed loss of Schlafen11 (SLFN11) expression could be restored by EZH2 inhibition ( Gardner et al., 2017 ), although this was not observed in a set of SCLC PDX models ( Drapkin et al., 2018 ). However, it might require a functional immune system to benefit from SLFN11 expression ( Mezzadra et al., 2019 ). Promising progress is being made with immunotherapy strategies showing a durable response in a small subset of patients ( Hellmann et al., 2018 ).…”

PAKC: A novel Panel of HLA class I Antigen presentation machinery Knockout Cells from the same genetic origin

“…During infection, cancer and autoimmunity, antigen presentation is enhanced by locally produced cytokines including IFN-γ. The IFN-γ signaling pathway is intact in HAP1 cells(26). Our experiments now showed that induction of IFN-γ signaling upregulates HLA-I mRNA and surface protein levels (Figure 2E and F).…”

Germline mutations and new copy number variants among 40 pediatric cancer patients suspected for genetic predisposition

“…Compared to normal adrenal gland tissues, all the three genes showed a reduced expression in NBL, mainly SLFN12 (Figure ). No genetic diseases have been associated with germline mutations in neither SLFN11 , SLFN12 or SLNF13 , but they are believed to regulate cell growth, to promote cell differentiation, to inhibit migration and invasion, to play a role in DNA repair …”

“…No genetic diseases have been associated with germline mutations in neither SLFN11, SLFN12 or SLNF13, but they are believed to regulate cell growth, to promote cell differentiation, to inhibit migration and invasion, to play a role in DNA repair. [9][10][11][12] In Pt-40, a duplication of the SOX4 was identified. This gene encodes for a transcription factor, which is markedly overexpressed in NBL (Figure 1), as well as in many types of cancer conferring poor prognosis.…”