Tumor-Infiltrating Lymphocytes (TILs) in Epithelial Ovarian Cancer: Heterogeneity, Prognostic Impact, and Relationship with Immune Checkpoints

Abstract

Epithelial ovarian cancers (EOC) are often diagnosed at an advanced stage with carcinomatosis and a poor prognosis. First-line treatment is based on a chemotherapy regimen combining a platinum-based drug and a taxane-based drug along with surgery. More than half of the patients will have concern about a recurrence. To improve the outcomes, new therapeutics are needed, and diverse strategies, such as immunotherapy, are currently being tested in EOC. To better understand the global immune contexture in EOC, several studies have been performed to decipher the landscape of tumor-infiltrating lymphocytes (TILs). CD8+ TILs are usually considered effective antitumor immune effectors that immune checkpoint inhibitors can potentially activate to reject tumor cells. To synthesize the knowledge of TILs in EOC, we conducted a review of studies published in MEDLINE or EMBASE in the last 10 years according to the PRISMA guidelines. The description and role of TILs in EOC prognosis are reviewed from the published data. The links between TILs, DNA repair deficiency, and ICs have been studied. Finally, this review describes the role of TILs in future immunotherapy for EOC.

Keywords: epithelial ovarian cancer (EOC); high-grade serous ovarian cancer (HGSOC); immune checkpoint inhibitors; peritoneum; tumor microenvironment; tumor-infiltrating lymphocytes (TILs).

Figure 1

Schematic diagram of the selection process for the studies included in this review. Review according to Moher [21], EOC: epithelial ovarian cancer.

Figure 2

Immunologic network in EOC: (A) simplified TIL view and location; (B) Main immune checkpoints studied in EOC. Simplified diagram of the main TILs described in the articles studied in this review. T cells infiltrating the stroma or tumor epithelium are identified via CD3, and/or CD4 and CD8. The subtypes of T cells, including TH1, TH2, TH17, TFH, and TREG, are illustrated. The main immune checkpoints described in this review are represented. iTILs: intra-tumoral, sTILs: stromal, B-TILs: B tumor-infiltrating lymphocytes, TCR: T cell receptor, PD-1: programmed-death 1, PD-L1: PD-1 ligand 1, PD-L2: PD-1 ligand 2, CTLA4: cytotoxic T-lymphocyte-associated protein 4, Tim-3: T cell immunoglobulin and mucin domain-containing protein 3, and LAG-3: lymphocyte activating gene 3.

Figure 3

Synthesis of the effects of TILs on prognosis in EOC. This figure summarizes the conclusion of the articles exploring the effects of TILs on EOC prognosis, either being evaluated in HES or via the study of a surface marker. B-TILs are mostly identified using CD20. H&E: hematoxylin and eosin, and B-TILs: B tumor-infiltrating lymphocytes.