Although recent findings indicate that targeting of inhibitory receptors on T cells can produce durable responses in some cancer patients despite the presence of advanced disease, the mechanisms controlling T-cell function in immunosuppressive tumors have not been well characterized. In a study reported in Nature, Zhou and colleagues showed that it is possible to systemically identify these inhibitory mechanisms in the tumor microenvironment.
The investigators constructed a pooled short hairpin RNA (shRNA) screen in which shRNAs targeting negative regulators become highly enriched in murine tumors after releasing a block on T-cell proliferation in response to tumor antigen recognition in vitro. The shRNAs were identified by deep sequencing of the shRNA cassette from T cells infiltrating tumor or control tissues. One of the target genes identified was Ppp2r2d, a regulatory subunit of the PP2A phosphatase family. Ppp2r2d knockdown in tumors reduced T-cell apoptosis and increased both T-cell proliferation and cytokine production.
The investigators concluded, “Key regulators of immune function can … be discovered in relevant tissue microenvironments.” ■