Ptpn2 loss increases tumor cell IFNγ signaling to enhance antigen presentation and antitumor immunity.
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.
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.
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