Myeloid suppression: TAMs, MDSCs & don't-eat-me signals
Tumours recruit the body's clean-up cells (macrophages and immature myeloid cells) and re-train them as bodyguards. They switch off T cells, build vessels, and, when a therapeutic antibody flags a cancer cell for eating, are told 'don't eat me' by CD47 on its surface.
Tumour and stromal CSF1, CCL2, CXCL1/2/8, VEGF, G-CSF and IL-6 recruit monocytes and neutrophils and expand myeloid-derived suppressor cells (PMN- and M-MDSC) from the bone marrow. In the tumour, hypoxia, lactate, IL-4/IL-13 and IL-10 polarise macrophages toward an immunosuppressive TAM state (TREM2+, SPP1+, MRC1+) that secretes IL-10, TGF-β, arginase, PGE2, expresses PD-L1, SIRPα and VISTA, and promotes angiogenesis and metastasis (TMEM doorways). MDSCs suppress via arginase, iNOS, ROS and PD-L1. CD47 on tumour cells binds SIRPα to block phagocytosis; magrolimab (anti-CD47) failed in AML/MDS after promising phase 1 data, but CD47 remains pursued with bispecifics. CSF1R inhibition (pexidartinib, vimseltinib in tenosynovial giant cell tumour) depletes TAMs but compensatory MDSC influx blunts it in cancer; CD40 agonists and TLR agonists reprogram; CXCR2 and CCR2 blockade limit recruitment; STAT3 and PI3Kγ inhibitors reprogram. Trained immunity (BCG) and engineered CAR-macrophages try to conscript the same cells for the attack.
In one picture
A landlord who hires the neighbourhood's own bouncers, pays them in sugar and lactate, and hangs a sign on every door that reads 'don't touch, friend' (CD47). The police (T cells) are stopped at the door by the bouncers, and the cleaners (macrophages) read the sign and leave.
Diagram
top- CSF1R inhibitors pexidartinib and vimseltinib (approved in tenosynovial giant cell tumour; disappointing in cancer)
- CD47/SIRPα: magrolimab failed in AML/MDS; next-generation bispecifics and SIRPα-Fc in trials
- CD40 agonists, TLR7/9 agonists, CXCR2/CCR2 blockade, PI3Kγ inhibitors as reprogrammers
- CAR-macrophages, trained innate immunity (BCG) and antibody engineering for ADCP
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