Update on the challenges and recent advances in cancer immunotherapy

Abstract

This overview provides an analysis of some of the immunotherapies currently in use and under investigation, with a special focus on the tumor microenvironment, which we believe is a major factor responsible for the general failure of immunotherapy to date. It is our expectation that combining immunotherapy with methods of altering the tumor microenvironment and targeting regulatory T cells and myeloid cells will yield favorable results.

Keywords: CTLA-4; PD-1; Tregs; exosomes; immunosuppression; myeloid-derived suppressor cells; tumor immunity; tumor microenvironment.

Figure 1

Innate and adaptive immunity in cancer and therapeutic interventions. Notes: The crosstalk between innate immunity (natural killers [NK], type 1 macrophages [M1], type 1 neutrophils [N1], mature dendritic cells [MDC], immature dendritic cells [IMDC]) and adaptive immunity is illustrated. Antigen (Ag) presentation association to augmentative methods like hyperthermia (HT), radiotherapy (RT), photodynamic therapy (PDT), and chemotherapy (CT) is also illustrated. Further, the important immunosuppressive effects of regulatory T cells (T_reg), myeloid-derived suppressor cells (MDSC), type 2 macrophages (M2) (also called tumor-associated macrophages [TAM]) and the transformation of neutrophils from type 1 with antitumoral capacity versus type 2 (N2), which have angiogenic and pro-tumoral activity are shown. Exosomes, which carry immunosuppressive information, are also depicted. The various treatment methods used to control T_reg, myeloid-derived suppressor cells, and exosomes are in the blue frames, whereas the active treatments with several autologous and allogenic cells cytokine-induced killer [CIK] cells and invariant natural killers [INKT] are illustrated in the green frames. Lymphokine-activated killer [LAK] cells are depicted as “+,” which indicates an augmentative effect, or “−,” which indicates an inhibitory effect. Abbreviations: ATRA, all-trans retinoic acid; CCL3, chemokine (C-C motif) ligand 3; CD, cluster of differentiation; COX2, cyclooxygenase-2; CTL, cytotoxic lymphocyte; CTLA-4, cytotoxic T-lymphocyte antigen 4; CXCL12, chemokine (C-X-C motif) ligand 12; DCs, dendritic cells; IDC, immature dendritic cells; IL, interleukin; PD-1, programmed cell death protein 1; PGE2, prostaglandin E2; ROS, reactive oxygen species; TGF-β, transforming growth factor beta; VEGF, vascular endothelial growth factor.