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Cell Dev. Biol."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> Escape from immunosurveillance is a hallmark of chronic lymphocytic leukemia (CLL) cells. In the protective niche of lymphoid organs, leukemic cells suppress the ability of T lymphocytes to form the immune synapse (IS), thereby hampering T-cell mediated anti-tumoral activities. By binding its cognate receptor PD-1 at the surface of T lymphocytes, the inhibitory ligand PD-L1, which is overexpressed in CLL cells, mediates the T-cell suppressive activities of CLL cells. However, the molecular mechanism underlying PD-L1 overexpression in CLL cells remains unknown. We have previously reported a defective expression of the pro-apoptotic and pro-oxidant adaptor p66Shc in CLL cells, which is causally related to an impairment in intracellular reactive oxygen species (ROS) production and to the activation of the ROS-sensitive transcription factor NF-\u03baB. The fact that PD-L1 expression is regulated by NF-\u03baB suggests a mechanistic relationship between p66Shc deficiency and PD-L1 overexpression in CLL cells.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> 62 treatment-naive CLL patients and 43 healthy donors were included in this study. PD-L1 and p66Shc expression was quantified in B cells by flow cytometry and qRT-PCR. IS architecture and local signaling was assessed by flow cytometry and confocal microscopy. CD8+ cell killing activity was assessed by flow cytometry.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Here we show that residual p66Shc expression in leukemic cells isolated both from CLL patients and from the CLL mouse model E\u03bc-TCL1 inversely correlated with PD-L1 expression. We also show that the PD-L1 increase prevented leukemic cells from forming ISs with T lymphocytes. Reconstitution of p66Shc, but not of a ROS-defective mutant, in both CLL cells and the CLL-derived cell line MEC-1, enhanced intracellular ROS and decreased PD-L1 expression. Similar results were obtained following treatment of CLL cells with H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> as exogenous source of ROS, that normalized PD-L1 expression and recovered IS formation.<\/jats:p><jats:p><jats:bold>Discussion:<\/jats:bold> Our data provide direct evidence that the p66Shc-deficiency-related ROS depletion in CLL cells concurs to enhance PD-L1 expression and provides a mechanistic basis for the suppression of T cell-mediated anti-tumoral functions in the immunosuppressive lymphoid niche.<\/jats:p>","DOI":"10.3389\/fcell.2024.1297116","type":"journal-article","created":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T04:42:47Z","timestamp":1705984967000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["p66Shc deficiency in CLL cells enhances PD-L1 expression and suppresses immune synapse formation"],"prefix":"10.3389","volume":"12","author":[{"given":"Ludovica","family":"Lopresti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagaja","family":"Capitani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Tatangelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmela","family":"Tangredi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gioia","family":"Boncompagni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Frezzato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Visentin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Marotta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Ciofini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Gozzetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Bocchia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livio","family":"Trentin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cosima T.","family":"Baldari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Patrussi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,1,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1111\/j.1365-2567.2011.03458.x","article-title":"The immunological synapse: a cause or consequence of T-cell receptor triggering?","volume":"133","author":"Alarc\u00f3n","year":"2011","journal-title":"Immunology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"524","DOI":"10.3390\/cancers12020524","article-title":"Clinico-biological implications of modified levels of cytokines in chronic lymphocytic leukemia: a possible therapeutic role","volume":"12","author":"Allegra","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B3","doi-asserted-by":"publisher","first-page":"584626","DOI":"10.3389\/fimmu.2020.584626","article-title":"Regulation of PD-L1 expression by NF-\u03baB in cancer","volume":"11","author":"Antonangeli","year":"2020","journal-title":"Front. 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