Adjuvants and myeloid-derived suppressor cells: enemies or allies in therapeutic cancer vaccination

Abstract

Adjuvants are a critical but largely overlooked and poorly understood component included in vaccine formulations to stimulate and modulate the desired immune responses to an antigen. However, unlike in the protective infectious disease vaccines, adjuvants for cancer vaccines also need to overcome the effect of tumor-induced suppressive immune populations circulating in tumor-bearing individuals. Myeloid-derived suppressor cells (MDSC) are considered to be one of the key immunosuppressive populations that inhibit tumor-specific T cell responses in cancer patients. This review focuses on the different signals for the activation of the immune system induced by adjuvants, and the close relationship to the mechanisms of recruitment and activation of MDSC. This work explores the possibility that a cancer vaccine adjuvant may either strengthen or weaken the effect of tumor-induced MDSC, and the crucial need to address this in present and future cancer vaccines.

Keywords: APC, antigen-presenting cells; ARG1, arginase 1; CTL, cytotoxic T lymphocytes; DC, dendritic cells; G-MDSC, granulocytic MDSC; GM-CSF, granulocyte macrophage colony-stimulating factor; MDSC; MDSC, myeloid-derived suppressor cells; Mo-MDSC, monocytic MDSC; NK, natural killer; NOS2, inducible nitric oxide synthase; TAM, tumor-associated macrophages; TLR ligands; TLR, Toll-like receptors; Treg, regulatory T cells; adjuvants; cancer; cytokines; immunotherapy.

Figure 1.

Schema of possible different interactions of cancer vaccine adjuvants with MDSC and potential outcomes on T cell activation. (A) After vaccine inoculation, adjuvants interact with tissue resident DC promoting their migration, activation and antigen presentation to T cells into the lymphoid organ. Additionally, adjuvants can also interact directly with DC or T lymphocytes inside the draining lymph node or spleen. Activated antigen-specific T cells most then migrate to inflamed tissue, which ideally would be the tumor and exert anti-tumor response. However, adjuvants that induce antigen depot could induce local inflammation into the site of injection that will trap effector T cells and recruit MDSC avoiding effective anti-tumor response. (B) Adjuvants can also directly induce MDSC and/or interact with those highly suppressive cells recruited by tumors. The interaction of the adjuvant with the tumor-induced MDSC can also modify tumor-specific antigen presentation by these cells at both the tumor and distant sites. (C) The interactions between adjuvants and MDSC have unpredictable consequences. A negative effect may be the activation and augmentation of the classical suppressive mechanisms of MDSC, their differentiation into M2 macrophages and their expansion of Treg populations. This outcome will reinforce the suppressive tumor microenvironment and will negatively impact the patient's outcome. In contrast, a positive outcome may be the inhibition of the suppressive capacity of MDSC and/or the induction of MDSC differentiation into DC and M1 macrophages, with the subsequent activation of anti-tumor T cell responses.