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1.
Sci Rep ; 11(1): 1399, 2021 01 14.
Article in English | MEDLINE | ID: mdl-33446805

ABSTRACT

SHP2 is a ubiquitous tyrosine phosphatase involved in regulating both tumor and immune cell signaling. In this study, we discovered a novel immune modulatory function of SHP2. Targeting this protein with allosteric SHP2 inhibitors promoted anti-tumor immunity, including enhancing T cell cytotoxic function and immune-mediated tumor regression. Knockout of SHP2 using CRISPR/Cas9 gene editing showed that targeting SHP2 in cancer cells contributes to this immune response. Inhibition of SHP2 activity augmented tumor intrinsic IFNγ signaling resulting in enhanced chemoattractant cytokine release and cytotoxic T cell recruitment, as well as increased expression of MHC Class I and PD-L1 on the cancer cell surface. Furthermore, SHP2 inhibition diminished the differentiation and inhibitory function of immune suppressive myeloid cells in the tumor microenvironment. SHP2 inhibition enhanced responses to anti-PD-1 blockade in syngeneic mouse models. Overall, our study reveals novel functions of SHP2 in tumor immunity and proposes that targeting SHP2 is a promising strategy for cancer immunotherapy.


Subject(s)
Immunity, Cellular , Neoplasm Proteins/immunology , Neoplasms, Experimental/immunology , Protein Tyrosine Phosphatase, Non-Receptor Type 11/immunology , Signal Transduction/immunology , T-Lymphocytes/immunology , Animals , Cell Line, Tumor , Gene Knockout Techniques , HEK293 Cells , Humans , Mice , Mice, Inbred BALB C , Neoplasm Proteins/genetics , Neoplasms, Experimental/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Signal Transduction/genetics
2.
Nat Med ; 25(1): 95-102, 2019 01.
Article in English | MEDLINE | ID: mdl-30559422

ABSTRACT

Interferons (IFNs) are cytokines that play a critical role in limiting infectious and malignant diseases 1-4 . Emerging data suggest that the strength and duration of IFN signaling can differentially impact cancer therapies, including immune checkpoint blockade 5-7 . Here, we characterize the output of IFN signaling, specifically IFN-stimulated gene (ISG) signatures, in primary tumors from The Cancer Genome Atlas. While immune infiltration correlates with the ISG signature in some primary tumors, the existence of ISG signature-positive tumors without evident infiltration of IFN-producing immune cells suggests that cancer cells per se can be a source of IFN production. Consistent with this hypothesis, analysis of patient-derived tumor xenografts propagated in immune-deficient mice shows evidence of ISG-positive tumors that correlates with expression of human type I and III IFNs derived from the cancer cells. Mechanistic studies using cell line models from the Cancer Cell Line Encyclopedia that harbor ISG signatures demonstrate that this is a by-product of a STING-dependent pathway resulting in chronic tumor-derived IFN production. This imposes a transcriptional state on the tumor, poising it to respond to the aberrant accumulation of double-stranded RNA (dsRNA) due to increased sensor levels (MDA5, RIG-I and PKR). By interrogating our functional short-hairpin RNA screen dataset across 398 cancer cell lines, we show that this ISG transcriptional state creates a novel genetic vulnerability. ISG signature-positive cancer cells are sensitive to the loss of ADAR, a dsRNA-editing enzyme that is also an ISG. A genome-wide CRISPR genetic suppressor screen reveals that the entire type I IFN pathway and the dsRNA-activated kinase, PKR, are required for the lethality induced by ADAR depletion. Therefore, tumor-derived IFN resulting in chronic signaling creates a cellular state primed to respond to dsRNA accumulation, rendering ISG-positive tumors susceptible to ADAR loss.


Subject(s)
Adenosine Deaminase/metabolism , Interferons/metabolism , RNA-Binding Proteins/metabolism , Animals , Cell Line, Tumor , Gene Expression Profiling , Humans , Membrane Proteins/metabolism , Mice, Nude , RNA, Small Interfering/metabolism , Signal Transduction , Suppression, Genetic , Xenograft Model Antitumor Assays
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