Victory and defeat in the induction of a therapeutic response through vaccine therapy for human and canine brain tumors: a review of the state of the art

Abstract

Anti-tumor immunotherapy using tumor lysate-based vaccines has made great advances over recent decades. Cancer vaccines aim to elicit adaptive immune responses through various pathways by providing tumor and tumor-associated antigens with an immune stimulant or adjuvant. These anti-tumor vaccines are therefore developed as personalized treatments. Utilizing tumors as a source of vaccine antigens in immunotherapy has demonstrated promising results with minimal toxicity. However, to date, researchers have failed to overcome the overpowering immune suppressive effects within the tumor microenvironment. Immune suppression occurs naturally via multiple mechanisms. These mechanisms serve an important homeostatic role restoring a normal tissue microenvironment following an inflammatory response. Due to these suppressive mechanisms and the inherent heterogeneity of tumors, it is imperative to then elicit and maintain a specific tumoricidal response if vaccine therapy or some other combination of reagents is chosen. In this review, we focus on the historical use of tumors as a source of antigens to elicit a tumoricidal response and the limitations encountered that prevent greater success in immunotherapy. We describe the advantages and disadvantages of various vaccines and their ineffectiveness due to tumor-induced immune suppression.

FIG. 1

Immunosuppressive tumor microenvironment. Cancer-associated inflammation up-regulates the production of myeloid cells from hematopoietic progenitors in the bone marrow. Common myeloid progenitor cells give rise to pre-dendritic cells (pre-DCs) and, under the influence of tumor-derived factors (e.g., VEGF, IL-6, and S100A9), myeloid-derived suppressor cells (MDSCs). These myeloid cells migrate into the tumor microenvironment in response to chemokines such as CCL3, CCL12, CXCL12, and β-defensins. VEGF and IL-6 activate STAT3 and C/EBPβ signaling in MDSCs, keeping them in an immature state. Tumor cells secrete cytokines/chemokines that recruit suppressive cells such as regulatory T cells (Treg), immature dendritic cells (iDC) MDSCs, and M2 macrophages. M2 macrophages and MDSCs inhibit T-cell responses through nutrient sequestration via arginase-I (Arg-I), reactive oxygen species (ROS) generation and nitric oxide (NO) as well as interference with trafficking into the tumor site. iDC are defective antigen presenters combined with low co-stimulatory molecule expression, they cause T-cell anergy and exhaustion. Tumors drive the formation of regulatory DCs suppressing effector T-cell functions through the secretion of the enzymes l-arginase and indolamine-2,3-dioxygenase (IDO), resulting in (1) the depletion of essential amino acids and the production of the tolerogenic metabolites adenosine and kynurenine; (2) release of immunosuppressive factors such as IL-10 and TGF-β; and (3) expression of co-stimulatory surface molecules, including PD-L1 and butyrophilins and induce regulatory T cells (Tregs).