Published OnlineFirst August 4, 2017; DOI: 10.1158/2159-8290.CD-RW2017-148

REsEARCh wATCh

Immunotherapy Major finding: Ptpn2 loss increases tumor cell IFNγ signaling to enhance antigen presentation and antitumor immunity .

Approach: A pooled in vivo genetic screen identifies genes that synergize with or cause resistance to immunotherapy .

Impact: Loss-of-function screens can identify genes such as PTPN2 that may be targeted to enhance immunotherapy .

PtPn2 Loss sEnsitiZEs tuMor cELLs to iMMunothErAPY Immune checkpoint blockade achieves durable responses in only a minority of patients with cancer, suggesting the need for additional approaches to improve its efficacy. To identify genes that might increase or decrease the response to immunotherapy, Manguso and colleagues performed a CRISPR/ Cas9-based pooled loss-of-function in vivo genetic screen evaluating the inactivation of 2,368 genes in melanoma cells that were transplanted into mice treated with immunotherapy. This screen identified known modulators of immunotherapy efficacy including the immune evasion molecules PD-L1 and CD47. Further, depletion of IFNγ pathway genes (Stat1, Jak1, Ifngr2, Ifngr1, or Jak2) promoted resistance to immunotherapy, with IFNγ-deficient tumors growing faster than wild-type tumors after anti–PD-1 or the irradiating tumor cell vaccine GVAX. In contrast, a number of genes whose depletion enhanced immunotherapy efficacy were uncovered, including genes involved in TNF signaling or NF-κB activation, antigen processing and presentation, inhibition of kinase signaling, or the ubiquitin-proteasome pathway. One of the top hits

was the protein tyrosine phosphatase Ptpn2, whose loss of function sensitized tumors to immunotherapy in models of melanoma and colon carcinoma. Conversely, overexpression of Ptpn2 conferred resistance to immunotherapy, and PTPN2 amplifications were detected in a subset of patients with immunotherapy-resistant tumors. Mechanistically, Ptpn2 loss increased the sensitivity to IFNγ signaling, resulting in increased tumor cell antigen presentation and enhanced sensitivity to cytotoxic CD8+ T cells. Consistent with these findings, loss of Ptpn2 suppressed the growth of immunotherapy-treated tumor cells, but disruption of IFNγ signaling prevented the growth suppression. The finding that PTPN2 loss sensitizes tumors to immunotherapy suggests the potential for therapeutic targeting of PTPN2 or other targets that that may enhance the efficacy of immunotherapy. n Manguso RT, Pope HW, Zimmer MD, Brown FD, Yates KB, Miller BC, et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature 2017;547:413–8.

neuroblastoma Major finding: Sympathetic noradrenergic and NCC-like transcriptional networks promote neuroblastoma heterogeneity .

Approach: Characterization of the neuroblastoma superenhancer landscape identifies core transcriptional circuitries .

Impact: Elucidation of neuroblastoma cell identities may provide insight into therapy design .

corE rEguLAtorY circuitriEs MEdiAtE nEurobLAstoMA hEtErogEnEitY Neuroblastoma is a pediatric cancer that arises in the peripheral sympathetic nervous system, most frequently in the adrenal glands, and exhibits  a great clinical  heterogeneity; however, mechanisms underlying neuroblastoma heterogeneity have not been  fully  elucidated because neuroblastoma harbors few somatic mutations. Recent evidence suggests that core transcriptional regulatory circuitries control the gene expression programs that determine cell identity. To identify core transcriptional networks that drive neuroblastoma  identity, Boeva and colleagues characterized the superenhancer landscapes of two human neural crest cell and 25 human neuroblastoma cell lines. Group I neuroblastoma cell lines exhibited a superenhancer pattern which was associated with transcription factor loci that control sympathetic noradrenergic cell identity.  Group II neuroblastoma cell lines and human neural crest cell lines exhibited highly similar superenhancer patterns, and four cell lines, some of which were phenotypically heterogeneous,  exhibited superenhancer features of both Groups I and II. Predictive algorithms demonstrated that Group I neuroblastomas are characterized by a noradrenergic core transcriptional regulatory module, including PHOX2B, HAND2, and GATA3, whereas Group II neuroblastomas are 932 | CANCER DISCOVERY September 2017

characterized by a neural crest cell–like core transcriptional regulatory module, including FOS and JUN. Similarly, analysis of primary neuroblastoma expression data showed that most neuroblastomas exhibit a heterogenous mixture of both Groups I and II modules. Further, PHOX2B, HAND2, and GATA3 were shown to simultaneously bind the same active superenhancer sites, suggesting that these are master transcription factors that drive noradrenergic neuroblastoma identity, and ablation of PHOX2B reduced noradrenergic neuroblastoma growth in vitro and in vivo. Paired pretreatment and relapsed neuroblastomas exhibited different module patterns, and chemotherapeutic drug treatment  of mixed neuroblastoma cells  in vitro  resulted in the enrichment of cells exhibiting the Group II neural crest cell–like module. These results identify the transcriptional core regulatory circuitries that drive neuroblastoma cell identity, reveal a novel aspect of tumor heterogeneity,  and may inform the design of therapeutic strategies. n Boeva V, Louis-Brennetot C, Peltier A, Durand S, Pierre-Eugène C, Raynal V, et al. Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries. Nature Genetics 2017 July 24 [Epub ahead of print]. www.aacrjournals.org

Downloaded from cancerdiscovery.aacrjournals.org on September 2, 2017. © 2017 American Association for Cancer Research. 00-CD-16-FM_Sep.indd 932

8/18/17 8:11 AM

Published OnlineFirst August 4, 2017; DOI: 10.1158/2159-8290.CD-RW2017-148

PTPN2 Loss Sensitizes Tumor Cells to Immunotherapy Cancer Discov 2017;7:932. Published OnlineFirst August 4, 2017.

Updated version

E-mail alerts Reprints and Subscriptions Permissions

Access the most recent version of this article at: doi:10.1158/2159-8290.CD-RW2017-148

Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected]. To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected].

Downloaded from cancerdiscovery.aacrjournals.org on September 2, 2017. © 2017 American Association for Cancer Research.

PTPN2 Loss Sensitizes Tumor Cells to Immunotherapy.

Ptpn2 loss increases tumor cell IFNγ signaling to enhance antigen presentation and antitumor immunity...
429KB Sizes 3 Downloads 18 Views