The Prognostic Value of Sex-Determining Region Y-Box 2 and CD8+ Tumor-Infiltrating Lymphocytes in Limited-Stage Small-Cell Lung Cancer

Abstract

<b><i>Background:</i></b> Sex-determining region Y-box 2 (SOX2) is a transcriptional factor that drives embryonic stem cells to neuroendocrine cells in lung development and is highly expressed in small-cell lung cancer (SCLC). However, the prognostic role of SOX2 and its relationship with tumor-infiltrating lymphocytes (TILs) has not been determined in SCLC. Herein, we assessed the expression of SOX2 and CD8+ TILs to obtain insights into the prognostic role of SOX2 and CD8+ TILs in limited-stage (LS)-SCLC. <b><i>Methods:</i></b> A total of 75 patients with LS-SCLC was enrolled. The SOX2 expression and CD8+ TILs were evaluated by immunohistochemistry. <b><i>Results:</i></b> High SOX2 and CD8+ TIL levels were identified in 52 (69.3%) and 40 (53.3%) patients, respectively. High SOX2 expression was correlated with increased density of CD8+ TILs (<i>p</i> = 0.041). Unlike SOX2, high CD8+ TIL numbers were associated with significantly longer progression-free survival (PFS; 13.9 vs. 8.0 months, <i>p</i> = 0.014). Patients with both high SOX2 expression and CD8+ TIL numbers (<i>n</i> = 29, 38.7%) had significantly longer PFS and overall survival (OS) compared to those from the other groups (median PFS 19.3 vs. 8.4 months; <i>p</i> = 0.002 and median OS 35.7 vs. 17.4 months; <i>p</i> = 0.004, respectively). Multivariate Cox regression analysis showed that the combination of high SOX2 expression and CD8+ TIL levels was an independent good prognostic factor for OS (HR = 0.471, 95% CI, 0.250–0.887, <i>p</i> = 0.02) and PFS (HR = 0.447, 95% CI, 0.250–0.801, <i>p</i> = 0.007) in SCLC. <b><i>Conclusions:</i></b> Evaluation of the combination of SOX2 and CD8+ TIL levels may be of a prognostic value in LS-SCLC.

The Relationship of SRY Determining Region Y Box 2 (SOX2) Immunohistochemical Expression with Stromal and Intratumoral TILs (Tumor Infiltrating Lymphocytes) in Patients with Ovarian Serous Tumors

“…Expression of SOX2 in cells that cause ovarian serous tumor spread allows tumors to withstand conventional chemotherapy and enhances their tumorigenicity77 However, a study by Le et al on small cell lung carcinoma that did not differentiate between intratumoral and stromal TILs found that high SOX2 and CD8+ TIL expression indicated high overall survival (OS) and progression free survival (PFS). 24…”

“…In a clinical study, high SOX2 expression in SCLC was significantly associated with poor prognosis. 14 Tumor Infiltrating Lymphocytes (TILs)consists of a heterogeneous collection of lymphoid cells that exhibit diverse antitumor activity and spatial distribution, characterized by the expression of several molecular biomarkers such as CD8, CD3, CD4, CD103 and PD-1. 15 Accumulation of TILs in ovarian cancer is prognostic for increased survival while increasingimmunosuppressive regulatory T cells (Tregs)associated with poor outcomes.…”

Tumor Microenvironment in Mixed Neuroendocrine Non-Neuroendocrine Neoplasms: Interaction between Tumors and Immune Cells, and Potential Effects of Neuroendocrine Differentiation on the Tumor Microenvironment

“…Various factors and components of the tumor microenvironment, including neoangiogenesis and the status of tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) related to tumor immunity, have been reported to play important roles in the clinical and/or biological behavior of cancer cases [14][15][16][17][18][19][20]. For example, the increased infiltration of CD8-positive lymphocytes into tumor tissues was reported to be associated with better clinical outcome of the patients, whereas that of CD4and Foxp3-positive lymphocytes with their worse prognosis [21][22][23][24][25][26][27]. da Silva et al also reported no significant differences in the intra-tumoral CD3-and CD8-positive lymphocyte infiltration status between gastrointestinal and pancreatic NETs [25].…”