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CAR-T cells trigger macrophage iNOS, limiting lymphoma attack
In experiments on mice, CAR‑T cells were found to induce macrophages to express the enzyme iNOS, which weakens the attack on lymphoma. On 31 August the peer‑reviewed version of an article on large B‑cell lymphoma described how CAR‑T cells activate iNOS in macrophages, producing nitric oxide. The researchers studied axi‑cel, a CAR‑T therapy in which patient T cells receive a receptor that recognizes the CD19 protein on lymphoma cells.
In a 2021 study the same group linked short‑lived responses to axi‑cel with tumor interferon signals and suppressive myeloid cells. Pretreatment biopsies showed that patients whose response did not persist had a higher relative proportion of M2‑like macrophages — immune cells capable of dampening the immune response — as revealed by RNA analysis. This association pointed to where the mechanism might lie.
In a laboratory model the authors combined mouse CAR‑T cells, B‑cell tumor cells, and M2‑like macrophages. After recognizing tumor cells, CAR‑T released IFN‑γ, a signaling protein of the immune system. IFN‑γ turned on iNOS in the macrophages; the enzyme produced nitric oxide, which slowed CAR‑T cell proliferation and weakened their ability to kill tumor cells.
The authors verified this pathway in two ways. The iNOS blocker L‑NIL and genetic deletion of the NOS2 gene in macrophages restored CAR‑T cells’ capacity to proliferate and kill tumor cells. Conversely, a nitric‑oxide‑donating compound suppressed their activity again.
In a mouse model of B‑cell lymphoma, the combination of CAR‑T and L‑NIL extended survival compared with CAR‑T alone. During leukapheresis — the procedure that isolates cells from blood to manufacture the therapy — patients whose response did not last had a higher fraction of CD14‑positive monocytes expressing iNOS. The authors view iNOS as a possible target for future clinical studies of CAR‑T.
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