Cancer Metastasis Rev (2011) 30:141–151 DOI 10.1007/s10555-011-9289-9
Tumor immune surveillance and ovarian cancer Lessons on immune mediated tumor rejection or tolerance Lana E. Kandalaft & Gregory T. Motz & Jaikumar Duraiswamy & George Coukos
Published online: 8 February 2011 # Springer Science+Business Media, LLC 2011
Abstract In the past few years, cancer immunotherapies have produced promising results. Although traditionally considered unresponsive to immune therapy, increasing evidence indicates that ovarian cancers are, in fact, immunogenic tumors. This evidence comes from diverse epidemiologic and clinical data comprising evidence of spontaneous antitumor immune response and its association with longer survival in a proportion of ovarian cancer patients; evidence of tumor immune evasion mechanisms and their association with short survival in some ovarian cancer patients; and finally pilot data supporting the efficacy of immune therapy. Below we will discuss lessons learned on the biology underlying ovarian cancer immune rejection or tolerance and we will discuss its association with clinical outcome. We will discuss the role of angiogenesis and the tumor endothelium on regulation of the antitumor immune response with a special emphasis on the role of vascular endothelial growth factor (VEGF) in the suppression of immunological processes, which control tumor progression and its unique crosstalk with endothelin systems, and how their interactions may shape the antitumor immune response. In addition, we will discuss mechanisms of tumor tolerance through the suppression or exhaustion of effector cells and how these could be countered in the clinic. We believe that understanding these pathways in the tumor microenvironment will lead to novel strategies for enhancing ovarian cancer immunotherapy. Keywords Ovarian cancer . Tumor immunoserveillance L. E. Kandalaft : G. T. Motz : J. Duraiswamy : G. Coukos (*) Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, PA 19104, USA e-mail:
[email protected] L. E. Kandalaft e-mail:
[email protected]
Epithelial ovarian carcinoma is the fourth most common cancer in women, and the most lethal gynecologic malignancy in the United States, accounting for approximately 22,000 new cases and 15,000 deaths per year. Due to incremental improvements in surgery and chemotherapy, the five-year survival rate has increased from 37% in the 1970 s to 45% in the 1990 s [1]. Based on large cooperative randomized clinical trials, the combination of carboplatin and paclitaxel still remains the best performing chemotherapy regimen. Yet, no substantial decrease has been seen in death rates, as the majority of patients relapse and die from their disease despite response to first-line therapy [2]. Thus novel therapeutic approaches are direly needed. Although traditionally considered unresponsive to immune therapy, increasing evidence indicates that ovarian cancers are, in fact, immunogenic tumors. This evidence comes from diverse epidemiologic and clinical data comprising evidence of spontaneous antitumor immune response and its association with longer survival in a proportion of ovarian cancer patients; evidence of tumor immune evasion mechanisms and their association with short survival in some ovarian cancer patients; and finally pilot data supporting the efficacy of immune therapy. Below we will discuss why we consider ovarian cancer an immunogenic tumor and we will review the biology underlying ovarian cancer immune rejection or tolerance and its association with clinical outcome. We will also discuss the multiple tumor-inducing immunosuppressive mechanisms such as the loss of tumor antigens, production of immunosuppressive cytokines such as transforming growth factor [beta] and interleukin 10, induction of immunosuppressive host immune cells including Tregs, myeloid-derived suppressor cells, and tumor-associated macrophages, and expression of immunosuppressive molecules such as Fas ligand and programmed cell death 1 ligand 1 (PD-L1) [3–7]. We will discuss the role of indoleamine 2,3-dioxygenase (IDO) in
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tumor-induced immune tolerance and we will focus on mechanisms at the tumor microenvironment that suppress the homing, extravasation, and effector function of effector T lymphocytes. Understanding these pathways at the tumor microenvironment will lead to novel strategies for enhancing ovarian cancer immunotherapy.
1 Ovarian cancer is an immunogenic tumor Many patients with ovarian cancers exhibit a spontaneous antitumor immune response. This fact has been demonstrated on various occasions. Tumor-specific T cells secreting interferon-gamma (IFN-γ) were reported in peripheral blood of patients with advanced ovarian carcinoma [8]. Perhaps the most convincing evidence of a spontaneous antitumor immune response in ovarian cancer is the presence of intraepithelial (intratumoral) tumorinfiltrating lymphocytes (TILs). We first reported in an Italian cohort that patients whose tumors had intratumoral TILs experienced longer progression-free and overall survival as compared to patients whose tumors lacked intraepithelial T-cells [9]. An important aspect revealed by studies done in our laboratory is that an improved clinical outcome depends on the infiltration of T cells specifically in tumor islets rather than stroma, as the mere presence of T cells in stroma alone did not predict better outcome. Survival at five years was 38% in patients whose tumors had intraepithelial T-cells (n=102) and 4.5% in patients lacking them (n=72), even after complete response to chemotherapy. The impact of intraepithelial CD3+ and/or CD8+ T cells has since been confirmed by multiple independent studies on ethnically and geographically diverse populations [7, 10–16]. For example, one study showed the strong predictive value specifically of intraepithelial CD8+ T cells, the subset of T cells that comprises mainly cytotoxic lymphocytes (CTL). Patients with higher frequencies of intraepithelial CD8+ T cells demonstrated improved survival compared with patients with lower CD8 + T cell frequencies (median survival 55 months versus 26 months; hazard ratio=0.33; P
