Nitsche, J. | bioRxiv Science

bioRxiv2026

Stemness overcomes IFNγ-induced antitumour exhaustion in human macrophages

Macrophages hold great promise for antitumour therapies (1-4), particularly owing to their ability to infiltrate solid tumours (5). Yet therapeutic success has been limited (6,7), because macrophages exhibit rapid exhaustion of antitumorigenic activity in the tumour (5,8,9). Here, we induced a stem-like self-renewal programme in human induced pluripotent stem cell (iPSC)-derived macrophages by deleting the self-renewal restricting transcription factors MAFB and MAF (MAF-DKO). Human MAF-DKO macrophages showed activated stem cell signatures, increased clonogenicity and proliferative potential. Increased self-renewal capacity was accompanied by enhanced mitochondrial fitness and invigorated energy metabolism. Importantly, these stemness features prevented exhaustion, cellular aging-associated parameters and loss of energy efficiency that are typically associated with proinflammatory macrophage activation. In addition, activated MAF-DKO macrophages showed a broad loss of IFN{gamma}-triggered immunosuppressive pathways (10,11), induced a super-activated state with robust cytotoxic activity and resisted exhaustion upon tumour cell exposure. Consequently, activated MAF-DKO macrophages showed intratumoral persistence with a stable antitumoral phenotype in vivo, conferred robust reduction of tumour burden and extended survival of tumour-bearing mice. Together, this demonstrates that the induction of stemness in human macrophages can overcome critical roadblocks of antitumour therapy by conferring resistance to activation-triggered exhaustion of antitumour activity in the TME.

immunology↗

bioRxiv2023

M-CSF induces a coordinated myeloid and NK cell differentiation program protecting against CMV after hematopoietic cell transplantation

Immunosuppressed patients are highly susceptible to viral infections. Therapies reconstituting autologous antiviral immunocompetence could therefore represent an important prophylaxis and treatment. Herpesviridae including cytomegalovirus (CMV) are a major cause of morbidity and mortality in patients after hematopoietic cell transplantation (HCT). Here, we show in a mouse model of HCT that macrophage colony-stimulating factor (M-CSF/CSF-1), a key cytokine for myeloid and monocytic differentiation, promoted rapid antiviral activity and protection from viremia caused by murine CMV. Mechanistically, M-CSF stimulated a coordinated myeloid and natural killer (NK) cell differentiation program culminating in increased NK cell numbers and production of granzyme B and interferon-{gamma}. This NK cell response depended upon M-CSF-induced myelopoiesis leading to IL15R-mediated presentation of IL-15 on monocytes. Furthermore, M-CSF also induced differentiation of plasmacytoid dendritic cells producing type I interferons, which supported IL-15-mediated protection. In the context of human HCT, M-CSF induced monopoiesis, increased IL15R expression on monocytes and elevated numbers of functionally competent NK cells in G-CSF-mobilized human hematopoietic stem and progenitor cells. Together, our data show that M-CSF induces an integrated multistep differentiation program that culminates in increased NK cell numbers and activation, thereby protecting graft recipients from CMV infection. Thus, our results identify a mechanism by which M-CSF-induced myelopoiesis can rapidly reconstitute antiviral activity during leukopenia following HCT. Key pointsO_LIM-CSF protects from lethal CMV viremia during leukopenia following hematopoietic cell transplantation, a vulnerable period of immunosuppression. C_LIO_LIEarly action of M-CSF on donor hematopoietic stem and progenitor cells rapidly reconstitutes antiviral immune responses. C_LIO_LIM-CSF stimulates a coordinated myeloid-NK cell-differentiation program resulting in increased NK cell numbers and activity. C_LIO_LIIncreased NK cell differentiation and activity depends on M-CSF-induced myelopoiesis generating IL-15-producing monocytes and I-IFN-producing pDCs. C_LIO_LIM-CSF also stimulates monopoiesis, IL15Ra expression in monocytes and functional NK cell differentiation in G-CSF-mobilized human PBMC. C_LIO_LINo impaired HCT engraftment or proclivity to graft-versus-host-disease by M-CSF. C_LIO_LIM-CSF could provide a single cytokine therapy addressing a major medical need, supporting current antiviral therapies during leukopenia following HCT. C_LI Visual abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/526105v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1b1398eorg.highwire.dtl.DTLVardef@39a9e3org.highwire.dtl.DTLVardef@1c08cc3org.highwire.dtl.DTLVardef@5996b4_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryM-CSF drives myeloid reconstitution to support CMV-directed natural killer cell competence via IL-15/I-IFN after hematopoietic cell transplantation.

immunology↗