Treatment Regimen, Surgical Outcome, and T-cell Differentiation Influence Prognostic Benefit of Tumor-Infiltrating Lymphocytes in High-Grade Serous Ovarian Cancer

Abstract

Purpose: 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.Experimental Design: Tissue microarray slides containing samples of 171 patients were analyzed for CD8 þ TIL by IHC.Freshly isolated CD8 þ TIL subsets were characterized by flow cytometry based on differentiation, activation, and exhaustion markers. Relevant T-cell subsets (CD27 þ ) were validated using IHC and immunofluorescence.Results: A prognostic benefit for patients with high intratumoral CD8þ 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 þ 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 þ TIL subset. In line with this, CD27 þ TIL were associated with an improved prognosis even in incompletely cytoreduced patients. Neither CD8 þ nor CD27 þ cell infiltration was of prognostic benefit in patients treated with neoadjuvant chemotherapy. Conclusions: 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. Clin Cancer Res; 22(3); 714-24. Ó2015 AACR.

CD103+ intraepithelial T cells in high-grade serous ovarian cancer are phenotypically diverse TCRαβ+ CD8αβ+ T cells that can be targeted for cancer immunotherapy

“…By contrast, CD103+ TIL were mainly found in the tumor epithelium (Figure 1A). Total CD103+ TIL numbers did not differ significantly between patients that received PS or NACT therapy (not shown), as reported previously for epithelial CD8+ TIL in this cohort [12]. In line with the observed epithelial distribution, total CD103+ TIL counts per mm 2 in these patients correlated strongly to intraepithelial CD3+ and CD8+ TIL (r=0.86; p<0.0001 and r=0.87; p<0.0001, respectively), but weaker to stromal CD3+ and CD8+ TIL (r=0.14; p=0.0008 and r=0.59; p<0.0001, respectively) (Figure 1B and 1C).…”

“…First, we confirmed the recent reports on the prognostic benefit of CD103+ TIL in HGSC [7,11] in an independent cohort of advanced-stage HGSC patients treated with either primary surgery and adjuvant chemotherapy (PS; n=84), or neo-adjuvant chemotherapy followed by interval surgery (NACT; n=102) [12]. CD3+, CD8+ and CD103+ TIL were present in tumors from most patients and the distribution of CD3+ and CD8+ TIL in tumor epithelium and stroma was similar (Figure 1A).…”

A Complex Network of Tumor Microenvironment in Human High-Grade Serous Ovarian Cancer

“…The presence of infiltrating immune cells in ovarian cancer was first reported nearly 40 years ago (15). Numerous studies elicited the favorable prognostic significance of increased numbers of various types of immune cells or overexpression of individual immune cell markers (9)(10)(11)(27)(28)(29). Our works revealed that the immune activation in HGSOC was an overall reaction of the host rather than a response of a single cell type or the expression alteration of a single gene.…”

The platelet-to-lymphocyte ratio as a predictor of patient outcomes in ovarian cancer: a meta-analysis

“…Platelets may release growth factors such as transforming growth factor b (TGF-b), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF), which may contribute to the growth, progression, and metastasis of the tumor by stimulating the proliferation of ovarian tumor cells 9 . Furthermore, a reduced lymphocyte count is an indicator of a reduced immune response, and it is correlated with higher mortality in patients with OC than in healthy controls or patients with benign diseases 10 . The PLR, which is inexpensively and easily determined in routine clinical practice, was proposed to be a highly efficient and independent prognostic biomarker for many tumors 7 .…”