The immune system exerts both tumor-destructive and tumor-protective functions. Mature dendritic cells (DCs), classically activated macrophages (M1), granulocytes, B lymphocytes, aβ and ɣδ T lymphocytes, natural killer T (NKT) cells, and natural killer (NK) cells may be implicated in antitumor immunoprotection. Conversely, tolerogenic DCs, alternatively activated macrophages (M2), myeloid-derived suppressor cells (MDSCs), and regulatory T (Tregs) and B cells (Bregs) are capable of suppressing antitumor immune responses. Anti-cancer vaccination is a useful strategy to elicit antitumor immune responses, while overcoming immunosuppressive mechanisms. Whole tumor cells or lysates derived thereof hold more promise as cancer vaccines than individual tumor-associated antigens (TAAs), because vaccinal cells can elicit immune responses to multiple TAAs. Cancer cell-based vaccines can be autologous, allogeneic or xenogeneic. Clinical use of xenogeneic vaccines is advantageous in that they can be most effective in breaking the preexisting immune tolerance to TAAs. To potentiate immunotherapy, vaccinations can be combined with other modalities that target different immune pathways. These modalities include 1) genetic or chemical modification of cell-based vaccines; 2) cross-priming TAAs to T cells by engaging dendritic cells; 3) T-cell adoptive therapy; 4) stimulation of cytotoxic inflammation by non-specific immunomodulators, toll-like receptor (TLR) agonists, cytokines, chemokines or hormones; 5) reduction of immunosuppression and/or stimulation of antitumor effector cells using antibodies, small molecules; and 6) various cytoreductive modalities. The authors envisage that combined immunotherapeutic strategies will allow for substantial improvements in clinical outcomes in the near future.
Keywords: ADCC, antibody-dependent cell cytotoxicity; APC, antigen-presenting cell; Ab, antibodies; BCG, Bacillus Calmette-Guérin; Breg, regulatory B cell; CAR, chimeric antigen receptor; COX, cyclooxygenase; CTA, cancer/testis antigen; CTL, cytotoxic T lymphocyte; CTLA-4, cytotoxic T lymphocyte antigen-4; DC, dendritic cell; DTH, delayed-type hypersensitivity; GITR, glucocorticoid-induced tumor necrosis factor receptor; GM-CSF, granulocyte-macrophage colony stimulating factor; HIFU, high-intensity focused ultrasound; IDO, indoleamine-2, 3-dioxygenase; IFN, interferon; IL, interleukin; LAK, lymphokine-activated killer; M, macrophage; M1, classically activated macrophage; M2, alternatively activated macrophage, MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; NK, natural killer (cell); PD-1, programmed death-1; PGE2, prostaglandin E2; RFA, radiofrequency ablation; RNS, reactive nitrogen species; ROS; TAA, tumor-associated antigen; TGF, transforming growth factor; TLR, toll-like receptor; TNF, tumor necrosis factor; Th, T-helper cell; Treg, regulatory T cell; VEGF, vascular endothelial growth factor; antitumor immunoprotection; cancer cell-based vaccines; combined immunotherapy; immunosuppression; reactive oxygen species.