Editorial: Prospects and Challenges for Immunotherapy of Ovarian Cancer—What Can We Learn from the Tumor Microenvironment?

Abstract

Although there has been a marked resurgence of optimism that tumor vaccination or active immunotherapy may hold the prospect of clinical benefit for ovarian cancer patients, this optimism has been tempered by an appreciation that ovarian cancer represents a paradigm for the art of immunological defense. The pathogenesis of ovarian cancer is characterized by the evolution of multiple immunosuppressive mechanisms in the tumor microenvironment, several of which correlate with increased morbidity and mortality in ovarian cancer patients. This issue of International Reviews of Immunology focuses on the immunology of ovarian cancer, with a particular emphasis on the role of antigen-presenting cells in shaping immunological stasis within the tumor microenvironment. An understanding of these mechanisms will likely guide the development of novel adjuvants to alleviate local immune suppression in support of clinically effective ovarian tumor vaccination.

Keywords :

• ovarian cancer
• tumor microenvironment
• vaccine therapy
• immunotherapy

In this issue of International Reviews of Immunology, we present six reviews by experienced and innovative investigators on the theme of ovarian tumor immunology and immunotherapy. This is not intended to present a comprehensive survey, but rather an idiosyncratic presentation of personal opinions on some of the current opportunities for ovarian tumor vaccination, and on the major barriers to successful immunotherapy that are presented by the pathology of the disease.

With respect to tumor vaccination, Chiang and colleagues provide a detailed discussion of whole tumor cell vaccination strategies and adjuvant treatments that may enhance immune responses, and Chiriva-Internati and others present some innovative approaches to dendritic cell (DC) vaccination, and open a discussion on the merits of Sp17, a cancer-testis antigen, as a therapeutic target for ovarian tumor vaccination or immunotherapy. It is this latter topic that has sparked the interest of many clinical investigators, in part due to the appreciation that DC can be powerful manipulators of tumor immunity, but also as a result of the recent FDA approval of Provenge® for the treatment of prostate cancer. Provenge® is an autologous DC vaccine formulation designed to stimulate immune responses against prostatic acid phosphatase, a key prostate tumor antigen. Provenge® constitutes a landmark as the first active cellular therapy (and DC vaccine) to be approved by the FDA for the treatment of cancer [1]. While this may be seen as the culmination of a long, drawn-out process, the hope is that Provenge® introduces a renaissance for cellular therapeutics in general (and DC vaccination in particular), leading to greater translational efforts to move laboratory and animal studies to clinical trials. DC vaccination has not yet been subject to extensive clinical testing for ovarian cancer, but there is a broad anticipation that clinical trials for DC vaccination will be conducted in the near future.

Notwithstanding the current (and, we believe, justifiable) enthusiasm for tumor vaccination and active cellular immunotherapy, a succession of groundbreaking experimental and clinical studies have made it starkly apparent that ovarian cancer deploys multiple mechanisms to regulate immunity in the tumor microenvironment. An understanding of the impact of ovarian tumor development and progression on the peritoneal immune system clearly forms a cornerstone for the elucidation of innovative strategies to circumvent local immunosuppression in support of ovarian tumor vaccination or immunotherapy. In the light of this knowledge, it is not surprising that the key role of antigen-presenting cells (APCs) in regulatory T-cell recruitment and ovarian tumor-associated immunosuppression is a recurring theme discussed by several authors in this issue.

Ovarian tumor infiltration by regulatory T cells (Treg) is now well recognized as a correlate of increased morbidity and mortality, a principle first established by the pioneering studies of Curiel and Zou, and discussed by several authors in this issue. Adjuvant treatments to abrogate Treg function in support of active tumor vaccination or immunotherapy are now receiving widespread attention, not only for ovarian cancer but also for other malignancies. Other correlates of immune dysfunction and poor clinical outcome in ovarian cancer include expression of the negative regulatory co-receptor B7-H1 by tumor cells and infiltrating myeloid dendritic cells, expression of B7-H4 by tumor-associated macrophages, and expression of indoleamine 2,3-dioxygenase (IDO). Strategies for depletion of myeloid suppressor cells, blockade of B7-H1 signaling, or inhibition of IDO activity are all currently under investigation as free-standing treatments or adjuvants for active immunotherapy for ovarian cancer.

The contrasting contributions of ovarian tumor-infiltrating APCs to disease pathogenesis and tumor immunity are discussed by Cailin Wilke and colleagues from the University of Michigan, and Iwona Wertel and colleagues from the Medical University of Lublin, Poland. Although tumor-infiltrating T cells have, perhaps, received more widespread attention, it is arguably the APCs that shape T-cell function in the microenvironment. Both myeloid DC and macrophages may contribute to local immune suppression, through expression of B7-H1 and B7-H4 (and other mechanisms, notably expression of IDO); they also have the capacity to induce Th17 cells, which may favor antitumor immunity in ovarian cancer patients. The influence of APC signaling on the reciprocal relationship between Treg and Th17 responses is drawing increased attention, since the relative levels of Treg and Th17 recruitment into the ovarian tumor microenvironment appear to have clear and opposing correlates with clinical outcome, with high IL-17 expression being associated with markedly improved overall survival. The precise role of Th17 responses in tumor immunity and pathogenesis has drawn some lively discussion of apparently conflicting results by several authors in this issue, since Th17 cells have also been associated with disease progression and angiogenesis in various experimental models. However, in the case of ovarian cancer, there is a strong case to be made for further investigation of the potential therapeutic benefits of vaccination strategies designed to boost Th17 responses. Knowledge of how to tip the balance between negative signals from APC resulting in Treg-associated immune suppression, and positive signals that promote Th17-associated antitumor immunity, may unlock the door to successful treatment.

Returning to the theme of tumor vaccination, Chiang and colleagues at the University of Pennsylvania present a detailed discussion of autologous or allogeneic whole tumor cell vaccines, a number of which have been tested in clinical trials for treatment of ovarian cancer and other malignancies. There are some obvious pros and cons to whole tumor cell vaccination—on the one hand, autologous tumors presumably lack intrinsic immunogenicity and, thus, require modification to meet this essential requirement. However, they have the key advantage of delivering multiple tumor antigens. Autologous vaccines will present antigens that match the disease, but need to be prepared from scratch for each patient. In contrast, allogeneic “off the shelf” vaccines may not always provide an ideal antigen match, but may have intrinsic adjuvant properties through the presentation of allogeneic HLA molecules and other antigens. The development of extrinsic adjuvants designed to boost immune function following tumor vaccination has also been afforded a comprehensive discussion by Chiang and colleagues. Their survey of current and experimental adjuvants for tumor vaccination highlights the multiplicity of options available for clinical testing; these include the innovative use of TLR agonists and agents that promote DC maturation, notably Flt-3 ligand. The potential ability of adjuvants to break immune tolerance to tumor-associated antigens and to alleviate disease-associated immunosuppression is likely to be a fertile area of investigation in the future.

The prospects for adoptive T cell immunotherapy have also received consideration from Thibodeaux and Curiel of the University of Texas Health Science Center, San Antonio. Notably, the innovative idea of using chimeric T cells engineered to express receptors that bind ovarian tumor antigens (e.g., folate receptor) has been tested in patients, but clinical responses have not been observed. These authors also discuss antibody therapies that target CA125, in particular clinical trials with an anti-idiotype antibody (Abagovomab) that has shown some clinical benefit in early clinical trials. This is an exciting observation, but results from Phase II/III clinical trials are not yet available.

Lastly, we must return to DC vaccination. Chiriva-Internati and colleagues at Texas Tech University and other institutions discuss the innovative use of adeno-associated virus (AAV) vectors for transduction of DC, and note that AAV itself promotes DC maturation, which is a critical step for effective stimulation of anti-tumor immunity. Furthermore, these authors consider the possibility that inhibition of p38 MAP kinase signaling in DC may diminish Treg activation and boost the efficacy of DC vaccination. In a very recent opinion, Chiriva-Internati and colleagues extended this theme to argue that inhibition of p38 MAP kinase signaling (and enhancement of the ERK MAP kinase pathway) in DC may play a pivotal role in the direction of Th17 responses to ovarian tumor antigens [2]. Given the recently established clinical association of Th17 responses with improved overall survival in ovarian cancer (as discussed by several authors in this issue), formulation of DC vaccines with the capacity to boost Th17 immunity in ovarian cancer patients holds considerable appeal for translational studies and possible clinical trials.

In closing, the multi-faceted reviews in this issue have highlighted our current knowledge of mechanisms involved in immune regulation in the ovarian tumor microenvironment, and presented a sober appreciation of the barriers to tumor vaccination. However, these discussions also hold the prospect that innovative adjuvant treatments to alleviate immunosuppression may enhance the therapeutic benefit of active immunotherapy. The rational design of future vaccine strategies for ovarian cancer should build on this foundation and should be firmly based on our understanding of immune regulation in ovarian tumor pathogenesis.