Abstract
Macrophages (Mφs) are instrumental regulators of the immune response whereby they acquire diverse functional phenotypes following their exposure to microenvironmental cues that govern their differentiation from monocytes and their activation. The complexity and diversity of the mycobacterial cell wall have empowered mycobacteria with potent immunomodulatory capacities. A heat-killed (HK) whole-cell preparation of Mycobacterium obuense (M. obuense) has shown promise as an adjunctive immunotherapeutic agent for the treatment of cancer. Moreover, HK M. obuense has been shown to trigger the differentiation of human monocytes into a monocyte-derived macrophage (MDM) type named Mob-MDM. However, the transcriptomic profile and functional properties of Mob-MDMs remain undefined during an activation state. Here, we characterized cytokine/chemokine release patterns and transcriptomic profiles of lipopolysaccharide (LPS)/interferon γ (IFNγ)-activated human MDMs that were differentiated with HK M. obuense (Mob-MDM(LPS/IFNγ)), macrophage colony-stimulating factor M-MDM(LPS/IFNγ)), or granulocyte/macrophage colony-stimulating factor (GM-MDM(LPS/IFNγ)). Mob-MDM(LPS/IFNγ) demonstrated a unique cytokine/chemokine release pattern (interleukin (IL)-10low, IL-12/23p40low, IL-23p19/p40low, chemokine (C-x-C) motif ligand (CXCL)9low) that was distinct from those of M-MDM(LPS/IFNγ) and GM-MDM(LPS/IFNγ). Furthermore, M-MDM(LPS/IFNγ) maintained IL-10 production at significantly higher levels compared to GM-MDM(LPS/IFNγ) and Mob-MDM(LPS/IFNγ) despite being activated with M1-Mφ-activating stimuli. Comparative RNA sequencing analysis pointed to a distinct transcriptome profile for Mob-MDM(LPS/IFNγ) relative to both M-MDM(LPS/IFNγ) and GM-MDM(LPS/IFNγ) that comprised 417 transcripts. Functional gene-set enrichment analysis revealed significant overrepresentation of signaling pathways and biological processes that were uniquely related to Mob-MDM(LPS/IFNγ). Our findings lay a foundation for the potential integration of HK M. obuense in specific cell-based immunotherapeutic modalities such as adoptive transfer of Mφs (Mob-MDM(LPS/IFNγ)) for cancer treatment.
Highlights
Macrophages (Mφs) are known for their exceptional degree of plasticity whereby they display diversified phenotypes and functions following exposure to various cues from the surrounding milieu [1]
The preactivation process whereby monocytes are differentiated into Mφs plays a dominant role in shaping the final activation state of Mφs irrespective of the adopted stimulus
HK whole-cell preparations of M. vaccae and M. obuense have a major advantage over Bacillus Calmette–Guérin (BCG) in terms of their favorable safety and tolerability
Summary
Macrophages (Mφs) are known for their exceptional degree of plasticity whereby they display diversified phenotypes and functions following exposure to various cues from the surrounding milieu [1]. M1-Mφs produce significant amounts of proinflammatory cytokines (e.g., interleukin (IL)-1β, IL-6, IL-12, IL-23, and tumor necrosis factor alpha (TNF-α)) and retain robust and antitumor capabilities in certain stages of cancer development and progression. M2-Mφs release substantial amounts of anti-inflammatory cytokines (e.g., IL-10 and transforming growth factor (TGF-β)) and contribute to tissue regeneration, angiogenesis, and tumor progression [2,3]. Following the maturation or differentiation stage, M1-like Mφs are stimulated with lipopolysaccharide (LPS) and interferon γ (IFNγ) to induce the activated M1-Mφ phenotype, while M2-like Mφs are stimulated with interleukin (IL)-4 ± IL-13, IL-10, TGF-β, immune complexes, or glucocorticoids to induce various activated M2-Mφ phenotypes [7,8]
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