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Tumor-related glucocorticoid excess is present in ~60% of patients and associated with particularly poor prognosis. Results of first clinical trials using immune checkpoint inhibitors were heterogeneous. Here we characterize tumor-infiltrating T lymphocytes (TILs) in ACC in association with glucocorticoids as potential explanation for resistance to immunotherapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed immunofluorescence analysis to visualize tumor-infiltrating T cells (CD3\n                      <jats:sup>+<\/jats:sup>\n                      ), T helper cells (CD3\n                      <jats:sup>+<\/jats:sup>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      ), cytotoxic T cells (CD3\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      ) and regulatory T cells (Tregs; CD3\n                      <jats:sup>+<\/jats:sup>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      FoxP3\n                      <jats:sup>+<\/jats:sup>\n                      ) in 146 ACC tissue specimens (107 primary tumors, 16 local recurrences, 23 metastases). Quantitative data of immune cell infiltration were correlated with clinical data (including glucocorticoid excess).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      86.3% of ACC specimens showed tumor infiltrating T cells (7.7 cells\/high power field (HPF)), including T helper (74.0%, 6.7 cells\/HPF), cytotoxic T cells (84.3%, 5.7 cells\/HPF) and Tregs (49.3%, 0.8 cells\/HPF). The number of TILs was associated with better overall survival (HR for death: 0.47, 95% CI 0.25 to 0.87), which was true for CD4\n                      <jats:sup>+<\/jats:sup>\n                      \u2212 and CD8\n                      <jats:sup>+<\/jats:sup>\n                      subpopulations as well. In localized, non-metastatic ACC, the favorable impact of TILs on overall and recurrence-free survival was manifested even independently of ENSAT (European Network for the Study of Adrenal Tumors) stage, resection status and Ki67 index. T helper cells were negatively correlated with glucocorticoid excess (Phi=\u22120.290, p=0.009). Patients with glucocorticoid excess and low TILs had a particularly poor overall survival (27 vs. 121 months in patients with TILs without glucocorticoid excess).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Glucocorticoid excess is associated with T cell depletion and unfavorable prognosis. To reactivate the immune system in ACC by checkpoint inhibitors, an inhibition of adrenal steroidogenesis might be pivotal and should be tested in prospective studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2019-000469","type":"journal-article","created":{"date-parts":[[2020,5,30]],"date-time":"2020-05-30T17:30:25Z","timestamp":1590859825000},"page":"e000469","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":104,"title":["Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma"],"prefix":"10.1136","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6315-4176","authenticated-orcid":false,"given":"Laura-Sophie","family":"Landwehr","sequence":"first","affiliation":[{"name":"Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital W\u00fcrzburg, W\u00fcrzburg, 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5873-8567","authenticated-orcid":false,"given":"Isabel","family":"Weigand","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7628-3161","authenticated-orcid":false,"given":"Matthias","family":"Kroiss","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital W\u00fcrzburg, W\u00fcrzburg, Germany"},{"name":"Comprehensive Cancer Center Mainfranken, University of W\u00fcrzburg, W\u00fcrzburg, 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