Prognostic and Predictive Role of Tumor-Infiltrating Lymphocytes (TILs) in Ovarian Cancer

Abstract

In the last decade, tumor-infiltrating lymphocytes (TILs) have been recognized as clinically relevant prognostic markers for improved survival, providing the immunological basis for the development of new therapeutic strategies and showing a significant prognostic and predictive role in several malignancies, including ovarian cancer (OC). In fact, many OCs show TILs whose typology and degree of infiltration have been shown to be strongly correlated with prognosis and survival. The OC histological subtype with the higher presence of TILs is the high-grade serous carcinoma (HGSC) followed by the endometrioid subtype, whereas mucinous and clear cell OCs seem to contain a lower percentage of TILs. The abundant presence of TILs in OC suggests an immunogenic potential for this tumor. Despite the high immunogenic potential, OC has been described as a highly immunosuppressive tumor with a high expression of PD1 by TILs. Although further studies are needed to better define their role in prognostic stratification and the therapeutic implication, intraepithelial TILs represent a relevant prognostic factor to take into account in OC. In this review, we will discuss the promising role of TILs as markers which are able to reflect the anticancer immune response, describing their potential capability to predict prognosis and therapy response in OC.

Role of histone methyltransferase SETDB1 in regulation of tumourigenesis and immune response

“…To date, 18 immune checkpoint inhibitors (ICIs) have been approved as cancer therapeutics, including 12 programmed cell death protein 1 (PD-1) monoclonal antibodies (pembrolizumab, nivolumab, cemiplimab, toripalimab, sintilimab, camrelizumab, tislelizumab, zimberelimab, penpulimab, dostarlimab, serplulimab and prolgolimab), five programmed cell death ligand 1 (PD-L1) monoclonal antibodies (atezolizumab, durvalumab, avelumab, envafolimab and sugemalimab), and one monoclonal antibody that blocks cytotoxic T-lymphocyte associated protein 4 (ipilimumab) ( Dhillon, 2021 ; Dhillon and Duggan, 2022 ; Lee, 2022 ; Markham, 2022 ; Yi et al, 2022 ). Despite considerable advancements, the response rate to ICIs is currently limited to 10%–25% in most tumour types ( Schoenfeld and Hellmann, 2020 ), and those with deficient immunogenic epitopes (low mutational burden) ( Verdegaal et al, 2016 ; Tran et al, 2017 ), impoverished tumour-infiltrating lymphocytes ( Galluzzi et al, 2018 ; Fanale et al, 2022 ), or profuse immunosuppressive factors (such as PD-L1, CD73, and indoleamine 2,3-dioxygenase 1) ( Young et al, 2016 ; Chen and Mellman, 2017 ; Song et al, 2021 ) are less likely to respond ( Galluzzi et al, 2018 ). Furthermore, initial ICI responders may develop acquired resistance ( Schoenfeld and Hellmann, 2020 ).…”

Low plasma PD-L1 levels, early tumor onset and absence of peritoneal carcinomatosis improve prognosis of women with advanced high-grade serous ovarian cancer

“…Despite this, recurrence rate still remains high and about 70% of women with advanced OC relapses with a poor prognosis [ 4 ]. Immunotherapy, which has already proved to be effective in other tumors, such as melanoma [ 5 ], renal cell carcinoma [ 6 , 7 ], and non small cell lung cancer [ 8 ], has also attracted attention in OC based on the finding that many OCs have tumor-infiltrating lymphocytes (TILs) [ 9 ]. However, the use of drugs directed against immune receptors and their ligands, so-called immune checkpoint inhibitors (ICIs), has not produced the expected results in OC [ 10 ].…”

“…One of the most studied immune checkpoint receptors is the programmed cell death protein 1 (PD-1), with its ligands, PD-L1 and PD-L2, which are involved in the activation, proliferation and cytotoxic secretion of T cells [ 9 ]. PD-L1 expression in tumor tissue correlates with the response to ICIs in different solid tumors, including Non-Small-Cell Lung Cancer (NSCLC) [ 8 ], and endometrial [ 13 ], triple-negative breast [ 14 ], head and neck tumors [ 15 ].…”

Can circulating PD-1, PD-L1, BTN3A1, pan-BTN3As, BTN2A1 and BTLA levels enhance prognostic power of CA125 in patients with advanced high-grade serous ovarian cancer?

“…Nevertheless, recurrence rate still remains elevated and about 70% of women with advanced OC relapses with a worse prognosis (6,7). Immunotherapy, whose effectiveness was demonstrated in other tumors, including non-small cell lung cancer (8,9), renal cell carcinoma (10,11), and melanoma (12), has not yielded the expected results in OC (13), despite the presence of tumorinfiltrating lymphocytes (TILs) (14)(15)(16).…”