Campbell, V. L. | bioRxiv Science

bioRxiv2026

LIMK Inhibition and Metformin Block Mitochondrial Transfer Overcoming Macrophage Driven Therapy Resistance in Acute Myeloid Leukaemia

Chemoresistance is a major contributor to poor clinical outcomes in AML patients and can arise from interactions between AML cells and the bone marrow microenvironment (BME). How immune cells, particularly macrophages (M{varphi}s), facilitate this process requires better clarification. This study shows that M2-like M{varphi}s protect AML cells from apoptosis induced by daunorubicin (DNR) and cytarabine (Ara-C). This protection occurs via co-culture and is linked to enhanced mitochondrial transfer from M{varphi}s to AML cells. M{varphi}s interacted with AML cells via tunneling nanotube (TNT)-like structures. Furthermore, inhibition of mitochondrial transfer using cytochalasin B reduced the protective effect, indicating that mitochondria mediate this process. M{varphi}s transferred functional mitochondria to AML cells as evidenced by enhanced metabolic capacity and reduced reactive oxygen species levels in AML cells under chemotherapy stress. TH-257 (LIMK inhibitor) and metformin blocked mitochondrial transfer and M{varphi}-driven chemoprotection. Moreover, increased transcript expression levels of RhoC and cofilin correlate with inferior overall survival in AML patients. These findings suggest that M2-like M{varphi}s contribute to chemoresistance through TNT-mediated mitochondrial transfer and the LIMK-Cofilin pathway, identifying potential therapeutic targets to circumvent chemoresistance in AML.

cancer biology↗

bioRxiv2024

Treponema pallidum periplasmic and membrane proteins are recognized by circulating and skin CD4+ T cells

BackgroundHistologic and serologic studies suggest the induction of local and systemic Treponema pallidum (Tp)-specific CD4+ T cell responses to Tp infection. We hypothesized that Tp-specific CD4+ T cells are detectable in blood and in the skin rash of secondary syphilis and persist in both compartments after treatment. MethodsPBMC collected from 67 participants were screened by IFN{gamma} ELISPOT response to Tp sonicate. Tp-reactive T cell lines from blood and skin were probed for responses to 88 recombinant Tp antigens. Peptide epitopes and HLA class II restriction were defined for selected antigens. ResultsWe detected CD4+ T cell responses to Tp sonicate ex vivo. Using Tp-reactive T cell lines we observed recognition of 14 discrete proteins, 13 of which localize to bacterial membranes or the periplasmic space. After therapy, Tp-specific T cells persisted for at least 6 months in skin and 10 years in blood. ConclusionsTp infection elicits an antigen-specific CD4+ T cell response in blood and skin. Tp-specific CD4+ T cells persist as memory in both compartments long after curative therapy. The Tp antigenic targets we identified may be high priority vaccine candidates.

immunology↗