The role of the immune system in limiting tumor growth, designated as cancer immunosurveillance [1
], has been first elucidated in mouse models of immune deficiency characterized by a high incidence of spontaneous and chemically induced tumors [2
]. Those studies have identified several components of the innate and adaptive immune response being responsible for tumor elimination, including αβ
], and NK cells [4
]. Reinforcing the role of cytotoxic T lymphocytes (CTLs) in the eradication of malignant cells, transgenic mice deficient in perforin, a component of the cytolytic granules of T and NK cells, are more susceptible to spontaneous and chemically induced tumors than their wild type counterparts [5
]. In humans, evidence on the role of the immune system in limiting tumor growth and progression is linked to observations indicating a positive correlation between the presence of tumor infiltrating CD8+ T-cells and good prognosis in various types of cancer. In colorectal cancer, for example, significantly higher levels of early memory and effector memory CD8+ T-cell infiltrates positively correlate with good clinical outcome, defined as absence of metastatic invasion, less advanced pathological stage, and increased survival [6
]. Similarly, the presence of intraepithelial tumor infiltrating CD8+ T-cells has been associated with the lack of tumor metastases in the draining lymph nodes of cervical cancer patients [8
]. In non-small cell lung carcinoma patients, increasing numbers of tumor infiltrating CD8+, CD20+, and CD4+ T lymphocytes have also been shown to significantly correlate with improved disease-specific survival [9
]. Altogether, these observations support a role for the immune system in controlling tumor burden and form the rationale for the development of vaccine-based interventions against cancer that rely on the stimulation of an effective antitumor immune response in the host.
The immune system, however, has two paradoxical roles in cancer. While various components of the innate and adaptive immune response are able to mediate tumor cell destruction, specific types of immune cells can also induce a protumor environment that favors tumor growth and the development of metastasis [10
]. Among the latter are, for example, regulatory T (Treg) cells [11
], tumor associated macrophages (TAM) [13
], and type 2 helper CD4+ (Th2) T-cells [15
]. These various immune cells have been shown to accumulate at the site of the tumor, negatively impacting the establishment of antitumor T-cell responses, that is, creating an immunosuppressive tumor environment.
Cancer cells themselves are also equipped with mechanisms that allow them to evade recognition by the immune system or to negatively affect the functionality of effector T-cells. In order to avoid immune recognition, tumor cells have been shown to downregulate antigen expression, components of the antigen-processing and presentation machinery, and expression of major histocompatibility complex (MHC) molecules [17
]. Decreased expression of costimulatory molecules of crucial importance to T-cell activation, and enhanced surface expression of molecules that negatively regulate activation of T-cells, such as PD-L1/B7-H1 and B7-H4, have also been demonstrated in various types of tumors [18
]. Cancer cells can also restrain the function of the immune system by secreting a milieu of soluble factors that ultimately inhibit the activation, proliferation, and differentiation of the various components of the immune response. Among these molecules are TGF-β
], IL-10 [22
], IL-13 [23
], and VEGF [24
The goal of vaccine-based cancer immunotherapy approaches is to induce a tumor-specific immune response that ultimately will reduce tumor burden by tipping the balance from a protumor to an antitumor immune environment (). This review discusses strategies employed in the field of cancer vaccines aimed at enhancing activation of tumor-specific T-cells with concurrent reduction of immunosuppression. Specifically, vaccine design, immune adjuvants, and multimodal approaches using vaccines in combination with other treatment modalities will be discussed here, with a particular emphasis on studies conducted at the National Cancer Institute, NIH.
Cancer vaccine strategies aimed at shifting the immune environment of a tumor from protumorigenic to antitumorigenic.