Tumor infiltrating lymphocytes in ovarian cancer

Abstract

The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and gene-engineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment.

Keywords: CAR, chimeric antigen receptor; IDO, indoleamine 2,3-dioxygenase; TIL, tumor infiltrating lymphocyte; Tregs, regulatory T-cell; immunosuppression; immunotherapy; ovarian cancer; prognostic factors; regulatory T-cells; tumor infiltrating lymphocytes.

Figure 1.

Inflammatory cells in Ovarian Tumor Milieu. Tumor cells are sampled by dendritic cells and antigen presenting cells and presented to T-cells, which are then activated to cytotoxic T-cells to directly destroy tumor cells or Helper T-Cells which can propagate the immune response through cytokine secretion and stimulation of other pro-inflammatory cells. To combat this inflammatory response, tumor cells release inhibitory cytokines such as TGF-β and IL-10 to manipulate APCs into transforming T-cells into Treg cells which can downregulate the anti-tumor inflammatory response and CCL22 which recruits Tregs to tumors. Endothelin-B and other molecules act on the tumor vasculature to block entry of inflammatory cells to the tumor milieu.

Figure 2.

Schema of Adoptive T-Cell Therapy in ovarian cancer in past clinical trials. T-cells from surgical specimens are extracted, selected for their tumor attacking ability, grown up in lab cultures using IL-2 as a stimulatory cytokine, and then re-injected into the patient.