Biology subjects

Wittling, M. C.

Publications and source records attributed to Wittling, M. C..

3 recordsLinked to original sources

bioRxiv2026

Confined T cell migration controls programmed cell death 1 expression

T cell immune checkpoint expression and dysfunction are attributed solely to molecular cues. We discover using microphysiological systems and in vivo models that transmigration through confined pores induces acute loss of programmed cell death 1 within minutes of surface immune checkpoint markers on CD8+ T cells through ubiquitin-mediated proteasomal degradation, corresponding with enhanced fitness and function. Such imprints and its underlying mechanism of programmed cell death 1 loss are conserved across species and applicable to human TIL and CAR T cells, and are correlative with disease outcomes in human melanoma. Our findings establish the diverse tissues landscapes that T cells traverse during immunosurveillance, and specifically transmigration, as a form of mechanical immune regulation, and reveal a mechano-modulatory strategy to improve the quality and persistence of engineered or patient-derived T cells for adoptive immunotherapy.

immunology↗

bioRxiv2025

Neoantigens drive adoptively transferred CD8 T cells to long-lived effectors mediated by lymph node trafficking

Adoptive transfer of neoantigen-reactive T lymphocytes mediates potent responses against solid tumors in patients while often limiting toxicity to normal tissues; however, the mechanisms governing the trafficking, activation, and superior antitumor function of infused T cells remain unknown. Using a clinically relevant TCR-transgenic T cell therapy model, we examined CD8 T cell responses to melanoma expressing either wild-type or mutated antigen. Neoantigen expression conferred robust tumor regression, durable cures, and long-term protective immunity. Mechanistically, T cells reacting to neoantigen exhibited enhanced cytokine and chemokine production, heightened effector function, and sustained persistence within the blood, tumor, and lymph nodes. Notably, trafficking through secondary lymphoid organs was necessary for T cell persistence and antitumor efficacy. These findings highlight the critical role of T cell trafficking to the lymph nodes in shaping neoantigen-specific antitumor responses and offers insight for improving adoptive cellular therapies.

cancer biology↗

bioRxiv2023

Distinct host preconditioning regimens differentially impact the antitumor potency of adoptively transferred Th17 cells.

BackgroundMechanisms by which distinct methods of host preconditioning impact the efficacy of adoptively transferred antitumor T helper cells is unknown. MethodsCD4+ T cells with a transgenic TCR that recognize TRP-1 melanoma antigen were polarized to the T helper 17 (Th17) phenotype and then transferred into melanoma-bearing mice preconditioned with either total body irradiation or chemotherapy. ResultsWe found that preconditioning mice with a non-myeloablative dose of total body irradiation (TBI of 5 Gy) was more effective than using an equivalently dosed non-myeloablative chemotherapy (CTX at 200 mg/kg) at augmenting therapeutic activity of anti-tumor TRP-1 Th17 cells. Anti-tumor Th17 cells engrafted better following preconditioning with TBI and regressed large established melanoma in all animals. Conversely, only half of mice survived long-term when preconditioned with CTX and infused with anti-melanoma Th17 cells. IL-17 and IFN-g produced by the infused Th17 cells, were detected in animals given either TBI or CTX preconditioning. Interestingly, inflammatory cytokines (G-CSF, IL-6, MCP-1, IL-5, and KC) were significantly elevated in the serum of mice preconditioned with TBI versus CTX after Th17 therapy. ConclusionsOur results indicate, for the first time, that the antitumor response, persistence, and cytokine profiles resulting from Th17 therapy are impacted by the specific regimen of host preconditioning. This work is important for understanding mechanisms that promote long-lived responses by ACT, particularly as CD4+ based T cell therapies are now emerging in the clinic.

cancer biology↗