Understanding the Impact of Myeloid Cells in CAR-T

Myeloid cells in CAR-T cell therapy represent a double-edged sword in modern oncology. While CAR-T cells directly target malignant antigens, the surrounding myeloid population significantly influences clinical outcomes. These cells modulate both the therapeutic efficacy and the safety profile of the treatment. Consequently, understanding these interactions is essential for advancing immunotherapy, particularly in solid tumors where success has been limited. Therefore, researchers are focusing on the complex interplay between engineered T cells and the innate immune system.

Myeloid Drivers of Treatment-Related Toxicities

A primary concern during CAR-T therapy is the development of systemic inflammation. Specifically, myeloid cells like macrophages and monocytes are central to Cytokine Release Syndrome (CRS). They release high levels of interleukin-6 (IL-6) and IL-1, which trigger severe physiological responses. Furthermore, these cells contribute to Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) by crossing the blood-brain barrier. Consequently, targeting myeloid-derived cytokines remains a critical strategy for toxicity management. Modern protocols now utilize IL-6 receptor antagonists and GM-CSF neutralization to mitigate these risks effectively.

Myeloid Cells in CAR-T Resistance and Enhancement

Solid tumors present a unique challenge due to their dense, immunosuppressive microenvironment. Myeloid-derived suppressor cells (MDSCs) often inhibit T-cell function through metabolic depletion and inhibitory signaling. However, certain myeloid subsets can also be reprogrammed to support anti-tumor responses. For instance, transitioning macrophages from an M2-like to an M1-like phenotype can enhance CAR-T persistence. Strategies such as CSF1R inhibition or TLR7 agonists are currently under clinical investigation. Thus, modulating the myeloid compartment could significantly boost the overall effectiveness of adoptive cell therapies.

FAQs

How do myeloid cells contribute to CRS during CAR-T therapy?

Myeloid cells, especially macrophages, are the primary producers of inflammatory cytokines like IL-6 and IL-1. When CAR-T cells activate, they stimulate these myeloid cells to release a massive wave of cytokines, leading to systemic inflammation.

Can myeloid cells be targeted to improve solid tumor outcomes?

Yes, strategies such as depleting MDSCs or using small molecules to repolarize tumor-associated macrophages can reduce immunosuppression. This allows CAR-T cells to infiltrate the tumor more effectively and maintain their cytotoxic function.

Disclaimer: This content is for informational and educational purposes only. It is not intended as medical advice or a substitute for professional clinical judgment. Refer to the latest local and national guidelines for clinical practice.

References

DeFranco G et al. The Conflicting Role of Myeloid Cells in CAR-T Cell Therapy. Cancer Res. 2026 Mar 12. doi: 10.1158/0008-5472.CAN-25-4817. PMID: 41817579.

Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021;11(4):69.

Giavridis T, et al. CAR T cell-induced cytokine release syndrome is mediated by macrophages and mitigated by IL-1 blockade. Nat Med. 2018;24(6):731-738.