Alternative immune checkpoints in immunoregulatory profile of cancer stem cells

Abstract

Tumor-mediated bypass of immune checkpoint inhibitor (ICI) therapy with anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1, also called B7-H1 or CD274) or anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) is a challenge of current years in the area of cancer immunotherapy. Alternative immune checkpoints (AICs) are molecules beyond the common PD-1, PD-L1 or CTLA-4, and are upregulated in patients who show low/no ICI responses. These are members of B7 family including B7-H2 (ICOS-L), B7-H3 (CD276), B7-H4 (B7x), V-domain immunoglobulin suppressor of T cell activation (VISTA), B7-H6, HHLA2 (B7-H5/B7-H7) and catabolic enzymes like indoleamine 2,3-dioxygenase 1 (IDO1), and others that are also contributed to the regulation of tumor immune microenvironment (TIME). There is also strong evidence supporting the implication of AICs in regulation of cancer stemness and expanding the population of cancer stem cells (CSCs). CSCs display immunoregulatory capacity and represent multiple immune checkpoints either on their surface or inside. Besides, they are active promoters of resistance to the common ICIs. The aim of this review is to investigate interrelations between AICs with stemness and differentiation profile of cancer. The key message of this paper is that targeted checkpoints can be selected based on their impact on CSCs along with their effect on immune cells. Studies published so far mainly focused on immune cells as a target for anti-checkpoints. Ex vivo engineering of extracellular vesicles (EVs) equipped with CSC-targeted anti-checkpoint antibodies is without a doubt a key therapeutic target that can be under consideration in future research.

Keywords: Alternative immune checkpoint (AIC); Cancer stem cell (CSC); Immune checkpoint inhibitor (ICI); Resistance; Tumor microenvironment (TME).

Fig. 1

The impact of alternative immune checkpoints (AICs) on cancer stem cells (CSCs) and their immunoregulatory roles. Orphan nuclear receptor subfamily 2 group F member 6 (NR2F6), lymphocyte activation gene-3 (Lag-3), T cell immunoglobulin mucin-3 (TIM-3) and indoleamine 2,3-dioxygenase (IDO) are AICs that are upregulated in CSCs and their overexpression promote immune evasion. CSCs also overexpress a number of B7 family members in order to evade from therapy. Conversion of cancer cells into CSCs and increasing the expansion of such cells within tumor microenvironment (TME) are key functions directed by the impact of AICs. B7–H3 blockade eliminates CSCs through increasing the infiltration of CD8⁺ T cells, and IDO1 inhibition reduces CSC proportion. Thus, AICs can be targeted and used as a supplementary to the common immune checkpoint inhibitors (ICIs) in strengthening anti-tumor immunity. VISTA, V-domain immunoglobulin suppressor of T cell activation. M2, macrophage type 2; and Treg, regulatory T cell.

Fig. 2

Implication of extracellular vesicles (EVs) for delivery of bispecific antibodies into tumor area. Here, tumor-derived EVs are extracted from blood and loaded with bispecific antibodies that have one inhibitor of a common checkpoint including anti-programmed death-1 (PD-1)/anti-programmed death-ligand 1 (PD-L1) in one side and an inhibitor of alternative immune checkpoint (AIC) in another side, particularly selecting AICs with activity on cancer stem cells (CSCs). The rationale for this targeted delivery is that tumor-derived EVs are attracted preferentially toward tumor area, and selection of CSC-targeted anti-checkpoints will reduce resistance rate and increase therapeutic durability.