Targeting the immune microenvironment for ovarian cancer therapy

Abstract

Ovarian cancer (OC) is an aggressive malignancy characterized by a complex immunosuppressive tumor microenvironment (TME). Immune checkpoint inhibitors have emerged as a breakthrough in cancer therapy by reactivating the antitumor immune response suppressed by tumor cells. However, in the case of OC, these inhibitors have failed to demonstrate significant improvements in patient outcomes, and existing biomarkers have not yet identified promising subgroups. Consequently, there remains a pressing need to understand the interplay between OC tumor cells and their surrounding microenvironment to develop effective immunotherapeutic approaches. This review aims to provide an overview of the OC TME and explore its potential as a therapeutic strategy. Tumor-infiltrating lymphocytes (TILs) are major actors in OC TME. Evidence has been accumulating regarding the spontaneous TILS response against OC antigens. Activated T-helpers secrete a wide range of inflammatory cytokines with a supportive action on cytotoxic T-cells. Simultaneously, mature B-cells are recruited and play a significant antitumor role through opsonization of target antigens and T-cell recruitment. Macrophages also form an important subset of innate immunity (M1-macrophages) while participating in the immune-stimulation context. Finally, OC has shown to engage a significant natural-killer-cells immune response, exerting direct cytotoxicity without prior sensitization. Despite this initial cytotoxicity, OC cells develop various strategies to induce an immune-tolerant state. To this end, multiple immunosuppressive molecules are secreted to impair cytotoxic cells, recruit regulatory cells, alter antigen presentation, and effectively evade immune response. Consequently, OC TME is predominantly infiltrated by immunosuppressive cells such as FOXP3+ regulatory T-cells, M2-polarized macrophages and myeloid-derived suppressor cells. Despite this strong immunosuppressive state, PD-1/PD-L1 inhibitors have failed to improve outcomes. Beyond PD-1/PD-L1, OC expresses multiple other immune checkpoints that contribute to immune evasion, and each representing potential immune targets. Novel immunotherapies are attempting to overcome the immunosuppressive state and induce specific immune responses using antibodies adoptive cell therapy or vaccines. Overall, the OC TME presents both opportunities and obstacles. Immunotherapeutic approaches continue to show promise, and next-generation inhibitors offer exciting opportunities. However, tailoring therapies to individual immune characteristics will be critical for the success of these treatments.

A disulfidptosis-related lncRNAs cluster to forecast the prognosis and immune landscapes of ovarian cancer

“…Immune cells and components within the TME have a dual role in both restraining tumor growth and facilitating immune evasion. These elements maintain a delicate balance and are vital for processes like extracellular matrix remodeling, the activation of cancer-related fibroblasts, and metabolic reprogramming ( Blanc-Durand et al, 2023 ). RNA methylation is known to play crucial roles in cancer development ( Xia et al, 2023 ).…”

Apoptosis, a Metabolic “Head-to-Head” between Tumor and T Cells: Implications for Immunotherapy

“…Several receptor kinase inhibitors and mAbs have been developed and are currently employed or undergoing clinical trials [ 215 ]. Then, besides inducing tumor vasculature normalization, targeting VEGF can mitigate Treg-mediated apoptosis of intra-tumor effector T cells and has been recognized as a crucial aspect in unraveling the complete potential of ICI blockade, thus holding the potential for improved treatment outcomes [ 216 ].…”

Recent advances in understanding the immune microenvironment in ovarian cancer

“…Both immune and targeted therapies against the TIME have shown promising results. Additionally, reversing the suppressive immune microenvironment in combination with antiangiogenic therapeutic regimens holds promise as a potential treatment for recurrent ovarian epithelial cancers ( 60 , 61 ). The TIME could influence the development and progression of OC, which can ultimately affect patient survival.…”