Biology subjects

Kolk, G.

Publications and source records attributed to Kolk, G..

3 recordsLinked to original sources

bioRxiv2025

PD-L1 ligation on NK cells induces a metabolic shift from glycolysis to fatty acid oxidation, enhancing tumor infiltration and control

PD-L1 blockade benefits even PD-L1-negative tumors, suggesting that non-tumor cells contribute to PD-L1 expression. Natural killer (NK) cells, vital mediators of innate immunity, vigorously express PD-L1 upon activation. We demonstrate that the ligation of PD-L1 on circulating and tumor-infiltrating NK cells with the therapeutic anti-PD-L1 antibody atezolizumab, soluble PD-1, or PD-1+ cells enhances NK cell-mediated tumor clearance via changes in metabolism, adhesion, and migration. PD-L1 engagement increases NK cell tumor infiltration via the CXCR3 pathway and cytoskeletal remodeling, supported by a metabolic shift from glycolysis to fatty acid oxidation (FAO). Loss of a key FAO enzyme, CPT1A, in NK cells abrogates the PD-L1-mediated anti-tumor effect, supporting a critical role for FAO in enhanced NK cell killing. The PD-L1-triggered shift away from glycolysis permits NK cells to remain highly effective at tumor killing in glucose-restricted TME. Taken together, PD-L1 ligation enhances NK cell cytotoxicity and tumor infiltration and contributes to NK resilience in challenging TME conditions, resulting in a more effective anti-tumor immunity. One sentence summaryPD-L1 engagement on NK cells enhances their tumor infiltration and cytotoxic activity by inducing a metabolic switch from glycolysis to fatty acid oxidation, enabling sustained function in the glucose-deprived tumor microenvironment.

immunology↗

bioRxiv2024

Tau Aggregation is Altered by Mutations in its Projection Domain

The intrinsically disordered microtubule-associated protein tau is known for its aberrant aggregation into neurofibrillary tangles as found in neuropathologies such as Alzheimers disease. This study compares three N-terminal isoforms of mutant R5L and of wild type tau to investigate how this mutation and the length of the projection domain affects aggregation behavior. Tau polymers in vitro were examined using atomic force microscopy imaging to compare tau filament lengths and morphologies. In a complementary analysis, the total amount of polymerization was analyzed using a Thioflavin S assay. We observed that the R5L mutation has a greater impact on filament length in shorter N-terminal isoforms of tau, whereas in longer N-terminal isoforms the mutation impacts the total amount of tau aggregation. These observations suggest that the R5L mutation affects the kinetic nucleation-elongation pathway of tau fibrillization, where the mutant impacts polymer nucleation in 2N and 1N isoforms, but has a more significant impact on elongation in the 0N isoform.

biophysics↗

bioRxiv2024

Engineered NKG2C+ NK-like T cells exhibit superior antitumor efficacy while mitigating cytokine release syndrome

Engineered T and NK cell therapies have widely been used to treat hematologic malignancies and solid tumors, with promising clinical results. Current chimeric antigen receptor (CAR) T cell therapeutics have, however, been associated with treatment-related adverse events such as cytokine release syndrome (CRS) and are prone to immunologic exhaustion. CAR-NK therapeutics, while not associated with CRS, have limited in vivo persistence. We now demonstrate that an NK-like TCR{beta}+ CD8 T cell subset, identified and expanded ex vivo through its expression of the activating receptor NKG2C (NKG2C+ NK-like T cells), can be transduced to express a second-generation CD19 CAR (1928z), resulting in superior tumor clearance, longer persistence and decreased exhaustion compared to conventional 1928z CAR+ CD8 T cells and 1928z CAR+ NK cells. Moreover, CAR-modified NKG2C+ NK-like T cells resulted in significantly reduced CRS compared to conventional CAR+ CD8 T cells. Similarly, NKG2C+ NK-like T cells engineered with a TCR targeting the NY-ESO-1 antigen exhibit robust tumor control and minimal exhaustion compared to TCR-engineered conventional CD8 T cells. These data establish NKG2C+ NK-like T cells as a robust platform for cell engineering, and offer a safer, more durable alternative to conventional CAR-T and CAR-NK therapies.

immunology↗