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 geneengineered 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. IntroductionTumor infiltrating lymphocytes (TILs) are present in ovarian cancer and are prognostic for increased survival. Given the impact of immunomodulatory regimens in melanoma, renal cell carcinoma, and lung cancer, and the recent elucidation of bona fide tumor-reactive TILs in ovarian cancer, the development of approaches that mobilize tumor-reactive TILs for successful eradication of ovarian cancer is now a high priority. In spite of strong rationale, attempts at administration of adoptive T cell transfer, immune enhancing antibody, and tumor immune environment conditioning in ovarian cancer have been minimal with some positive results reported in patients. In light of the recent development of new immunotherapeutic agents and treatment regimens that bolster host TIL activity, we review the current understanding of the immunobiology of human ovarian cancer including the impact of TIL subset accumulation on ovarian cancer survival and the effect of immune activation in the tumor microenvironment, and conclude that a new line of cancer immunotherapy investigations is warranted in ovarian carcinoma.Ovarian cancer is the second most common and most lethal gynecologic malignancy in the United States with approximately 22,000 new cases and 14,000 deaths expected in 2013.1 Ovarian cancer is often diagnosed at an advanced stage, with the large majority of new cases spread past the primary site. Since there are no current recommendations for ovarian cancer screenings, most efforts at combating ovarian cancer have been targeted at the discovery of new treatments rather than preventative measures. Currently, surgical staging and cytoreduction followed by chemotherapy is the mainstay of treatment, although in some cases neo-adjuvant chemotherapy is attempted.2 The standard for surgical staging consists of total hysterectomy and bilateral salpingooophrectomy with pelvic and para-aortic lymph node di...

The prognostic value of tumor-infiltrating T lymphocytes in ovarian cancer

“…Indeed, the prognostic value of intraepithelial Treg infiltration in ovarian cancer is still in debate [5, 30]. Some studies showed that Treg infiltration was associated with decreased overall survival in ovarian cancer [17, 30].…”

The Prognostic Value of Tumor-infiltrating Lymphocytes in Hepatocellular Carcinoma: a Systematic Review and Meta-analysis

“…Some studies assessed the prognostic value of tumor-infiltrating lymphocytes in various types of tumors, such as breast cancer, gastric cancer, non-small cell lung cancer, and ovarian cancer 38–41 . Many results indicated that TILs may be clinically significant prognostic biomarkers.…”

Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies

“…The diverse array of immune evasion mechanisms employed by tumors highlights the necessity for combination and synergistic therapies. Here, we discuss major drivers of T cell dysfunction in the context of three solid tumors: 1) melanoma, in which T cell responses exist and frequently can be enhanced to mediate anti-tumor activity (Rosenberg and Restifo, 2015), 2) ovarian cancer, in which potentially beneficial T cell responses exist in a subset of patients, but have proven difficult to augment (Santoiemma and Powell, 2015) and 3) PDA, in which endogenous T cell responses are rare (Emmrich et al, 1998; Ene-Obong et al, 2013; von Bernstorff et al, 2001). …”