Abstract
Tumor-infiltrating lymphocytes (TIL) are associated with a better prognosis in high-grade serous ovarian cancer (HGSC). However, it is largely unknown how this prognostic benefit of TIL relates to current standard treatment of surgical resection and (neo-)adjuvant chemotherapy. To address this outstanding issue, we compared TIL infiltration in a unique cohort of patients with advanced-stage HGSC primarily treated with either surgery or neoadjuvant chemotherapy. Tissue microarray slides containing samples of 171 patients were analyzed for CD8(+) TIL by IHC. Freshly isolated CD8(+) TIL subsets were characterized by flow cytometry based on differentiation, activation, and exhaustion markers. Relevant T-cell subsets (CD27(+)) were validated using IHC and immunofluorescence. A prognostic benefit for patients with high intratumoral CD8(+) TIL was observed if primary surgery had resulted in a complete cytoreduction (no residual tissue). By contrast, optimal (<1 cm of residual tumor) or incomplete cytoreduction fully abrogated the prognostic effect of CD8(+) TIL. Subsequent analysis of primary TIL by flow cytometry and immunofluorescence identified CD27 as a key marker for a less-differentiated, yet antigen-experienced and potentially tumor-reactive CD8(+) TIL subset. In line with this, CD27(+) TIL were associated with an improved prognosis even in incompletely cytoreduced patients. Neither CD8(+) nor CD27(+) cell infiltration was of prognostic benefit in patients treated with neoadjuvant chemotherapy. Our findings indicate that treatment regimen, surgical result, and the differentiation of TIL should all be taken into account when studying immune factors in HGSC or, by extension, selecting patients for immunotherapy trials.
Highlights
Epithelial ovarian cancer (EOC) is the most deadly gynecologic malignancy with an overall 5-year survival of 38% to 40% [1].Note: Supplementary data for this article are available at Clinical Cancer Research Online.M.C.A
Our findings indicate that treatment regimen, surgical result, and the differentiation of tumor-infiltrating lymphocytes (TIL) should all be taken into account when studying immune factors in high-grade serous carcinoma (HGSC) or, by extension, selecting patients for immunotherapy trials
We demonstrate that the prognostic value of TIL in advanced-stage HGSC is variable for patients primarily treated with surgery or neoadjuvant chemotherapy (NACT)
Summary
Primary surgery and NACT cohort From a total of 265 patients, the tissue in FFPE blocks obtained at primary or interval surgery was available to construct the TMA. Within the group without residual tissue, a clear survival benefit was observed for patients who had a high infiltration of CD8þ T cells (Fig. 1E; P 1⁄4 0.028), suggesting a role of CD8þ in tumor immunosurveillance. In order to determine whether the chemotherapy had influenced the infiltration of CD27þ TIL, we compared cell numbers between the two data sets and found no differences between the two cohorts (Fig. 4B; P 1⁄4 0.891). To confirm the value of CD27 over CD8 as a marker for prognosis in HGSC, we performed a multivariate Cox regression analysis (Table 2), including all variables shown to be associated with survival in univariate analyses (FIGO stage, surgery result and age) In this model, only surgical result [HR: 1.50; 95% confidence interval (CI): 1.24–1.80] and CD27þ cell infiltration (HR: 0.23; 95%CI: 0.10–0.56) proved to be of prognostic value. Whereas CD8þ TIL provide survival benefit only in patients where no macroscopic disease is present after cytoreductive surgery
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