Targeting the tumor microenvironment to enhance antitumor immune responses

Abstract

The identification of tumor-specific antigens and the immune responses directed against them has instigated the development of therapies to enhance antitumor immune responses. Most of these cancer immunotherapies are administered systemically rather than directly to tumors. Nonetheless, numerous studies have demonstrated that intratumoral therapy is an attractive approach, both for immunization and immunomodulation purposes. Injection, recruitment and/or activation of antigen-presenting cells in the tumor nest have been extensively studied as strategies to cross-prime immune responses. Moreover, delivery of stimulatory cytokines, blockade of inhibitory cytokines and immune checkpoint blockade have been explored to restore immunological fitness at the tumor site. These tumor-targeted therapies have the potential to induce systemic immunity without the toxicity that is often associated with systemic treatments. We review the most promising intratumoral immunotherapies, how these affect systemic antitumor immunity such that disseminated tumor cells are eliminated, and which approaches have been proven successful in animal models and patients.

Figure 1. Schematic representation of tumor environment; interactions between tumor and immune cells

Different immune cell types mediate the destruction of tumor cells such as NK and T cells. In contrast to the direct effects exerted by NK cells, adaptive T-cell responses are generated once DCs have primed T cells in the draining lymph nodes. However, the tumor modifies the environment in order to disrupt these antitumor effects and recruits and stimulates suppressive immune cells. Abbreviations: CTL (Cytotoxic T Lymphocytes); DC (Dendritic Cell); MDSC (Myeloid-Derived Suppressor Cell); NK cell (Natural Killer cell); TAA (Tumor-Associated Antigen); TAM (Tumor-Associaded Macrophages); TDLN (Tumor-Draining Lymph Nodes); Treg (Regulatory T cells).

Figure 2. mRNA encoding for TriMix as a tool for intratumoral immunization

Upon intratumoral delivery, mRNA encoding TriMix (CD40L, caTLR4 and CD70) is taken up by DCs. These tumor-residing DCs pick up tumor antigens, mature upon translation of the TriMix mRNA and migrate towards the tumor-draining lymph nodes. Fully matured DCs induce tumor-specific CTLs that in turn migrate back to the tumor. Abbreviations: CTL (Cytotoxic T Lymphocytes); DC (Dendritic Cell); TDLN (Tumor-Draining Lymph Nodes).

Figure 3. mRNA encoding for Fβ² as a tool for intratumoral immunomodulation

mRNA encoding Fβ², a fusokine consisting of IFN-β fused to the ectodomain of the TGF-β receptor II, is taken up by tumor-residing DCs. These DCs serve as factories to produce therapeutic amounts of the fusokine. This fusokine creates a CTL-friendly environment and as such contributes to antitumor immunity. Abbreviations: CTL (Cytotoxic T Lymphocytes); DC (Dendritic Cell); IFN-β (Interferon-β); TGF-β (Transforming-Growth Factor-β).

Figure 4. Combination therapy: the way forward

The combination of cytotoxic pharmaceutics is a standard strategy in clinical oncology to increase clinical responses. A similar paradigm has emerged in cancer immunotherapy. It is believed that strategies that aim at inducing tumor-specific T cells should be combined with strategies that counteract mechanisms devised by the tumor and its environment to down-regulate T cell-mediated tumor cell rejection. We contend that smart combinations of the strategies discussed in this review, in particular immunization and immunomodulation, are key to the eradication of some of the currently difficult to treat tumors.