Exploiting the Immunomodulatory Properties of Chemotherapeutic Drugs to Improve the Success of Cancer Immunotherapy

Abstract

Cancer immunotherapy is gaining momentum in the clinic. The current challenge is to understand why a proportion of cancer patients do not respond to cancer immunotherapy, and how this can be translated into the rational design of combinatorial cancer immunotherapy strategies aimed at maximizing success of immunotherapy. Here, we discuss how tumors orchestrate an immunosuppressive microenvironment, which contributes to their escape from immune attack. Relieving the immunosuppressive networks in cancer patients is an attractive strategy to extend the clinical success of cancer immunotherapy. Since the clinical availability of drugs specifically targeting immunosuppressive cells or mediators is still limited, an alternative strategy is to use conventional chemotherapy drugs with immunomodulatory properties to improve cancer immunotherapy. We summarize the preclinical and clinical studies that illustrate how the anti-tumor T cell response can be enhanced by chemotherapy-induced relief of immunosuppressive networks. Treatment strategies aimed at combining chemotherapy-induced relief of immunosuppression and T cell-boosting checkpoint inhibitors provide an attractive and clinically feasible approach to overcome intrinsic and acquired resistance to cancer immunotherapy, and to extend the clinical success of cancer immunotherapy.

Keywords: anti-tumor immunity; cancer immunotherapy; chemotherapy; immune checkpoint blockade; immunosuppression; tumor microenvironment.

Figure 1

Establishment of the immune microenvironment during breast cancer progression in a conditional mouse model for mammary tumorigenesis. Female K14Cre;Cdh1^F/F;Trp53^F/F mice develop de novo invasive mammary tumors that closely resemble human invasive lobular carcinoma (19). Immunohistochemical staining on mammary tissue from K14Cre;Cdh1^F/F;Trp53^F/F mice obtained during different stages of mammary tumor progression. From top to bottom are represented wild-type mammary gland (top), early lesion (middle), established mammary tumor (bottom). From left to right, identification of different immune cell populations by H&E, F4/80 (macrophages), Ly6G (neutrophils), CD3 (total T cells), and FOXP3 (regulatory T cells) staining showing the dynamics of the tumor microenvironment. Arrowheads indicate FOXP3⁺ nuclei. Scale bar 100 μm.

Figure 2

Combination strategies aimed at relieving the immunosuppressive tumor microenvironment with chemotherapy and potentiating cytotoxic T cells with immune checkpoint inhibitors. The tumor microenvironment is characterized by the presence of various immune cell types, including different subsets of adaptive immune cells and TAMs, MDSCs, and T_regs. The latter dampens the anti-cancer activity of T cells through several mechanisms. Moreover, cancer cells and myeloid cells express PD-L1/PD-L2 and APCs express CD80/CD86. Binding of these molecules to PD-1 and CTLA-4 respectively, expressed on T cells, results in inhibitory signals that counteract T cell activation and function. The immunomodulatory properties of different types of chemotherapeutic drugs can be exploited to enhance anti-tumor immunity. By optimally matching the immunomodulatory features of specific chemotherapeutic drugs with the T cell-boosting effect of immune checkpoint inhibitors, the efficacy of immunotherapy might be improved.