Biology subjects

Hsu, K. C.

Publications and source records attributed to Hsu, K. C..

5 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

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↗

bioRxiv2024

CAR-engineered lymphocyte persistence is governed by a FAS ligand/FAS auto-regulatory circuit

Chimeric antigen receptor (CAR)-engineered T and NK cells can cause durable remission of B-cell malignancies; however, limited persistence restrains the full potential of these therapies in many patients. The FAS ligand (FAS-L)/FAS pathway governs naturally-occurring lymphocyte homeostasis, yet knowledge of which cells express FAS-L in patients and whether these sources compromise CAR persistence remains incomplete. Here, we constructed a single-cell atlas of diverse cancer types to identify cellular subsets expressing FASLG, the gene encoding FAS-L. We discovered that FASLG is limited primarily to endogenous T cells, NK cells, and CAR-T cells while tumor and stromal cells express minimal FASLG. To establish whether CAR-T/NK cell survival is regulated through FAS-L, we performed competitive fitness assays using lymphocytes modified with or without a FAS dominant negative receptor ({Delta}FAS). Following adoptive transfer, {Delta}FAS-expressing CAR-T and CAR-NK cells became enriched across multiple tissues, a phenomenon that mechanistically was reverted through FASLG knockout. By contrast, FASLG was dispensable for CAR-mediated tumor killing. In multiple models, {Delta}FAS co-expression by CAR-T and CAR-NK enhanced antitumor efficacy compared with CAR cells alone. Together, these findings reveal that CAR-engineered lymphocyte persistence is governed by a FAS-L/FAS auto-regulatory circuit.

immunology↗

bioRxiv2023

Single-Cell Profiling Reveals a Naive-Memory Relationship between CD56bright and Adaptive Human Natural Killer Cells

Development of antigen-specific memory upon pathogen exposure is a hallmark of the adaptive immune system. While natural killer (NK) cells are considered part of the innate immune system, humans exposed to the chronic viral pathogen cytomegalovirus (CMV) often possess a distinct NK cell population lacking in individuals who have not been exposed, termed "adaptive" NK cells. To identify the "naive" population from which this "memory" population derives, we performed phenotypic, transcriptional, and functional profiling of NK cell subsets. We identified immature precursors to the Adaptive NK cells that are equally present in both CMV+ and CMV-individuals, resolved an Adaptive transcriptional state distinct from most mature NK cells and sharing a common gene program with the immature CD56bright population, and demonstrated retention of proliferative capacity and acquisition of superior IFN{gamma} production in the Adaptive population. Furthermore, we distinguish the CD56bright and Adaptive NK populations by expression of the transcription factor CXXC5, positioning these memory NK cells at the inflection point between innate and adaptive lymphocytes.

immunology↗

bioRxiv2020

Cytotoxic lymphocytes use mechanosurveillance to target biophysical vulnerabilities in cancer

Immune cells identify cancer cells by recognizing characteristic biochemical features indicative of oncogenic transformation. Cancer cells have characteristic mechanical features, as well, but whether these biophysical properties also contribute to destruction by the immune system is not known. In the present study, we found that enhanced expression of myocardin related transcription factors (MRTFs), which promote migration and metastatic invasion, paradoxically compromised lung colonization by melanoma and breast carcinoma cells in an immune-mediated manner. Cancer cells with increased MRTF signaling were also more sensitive to immune checkpoint blockade therapy in mice and humans. The basis for this vulnerability was not biochemical, but biophysical. MRTF expression strengthened the actin cytoskeleton, increasing the rigidity of cancer cells and thereby making them more vulnerable to cytotoxic T lymphocytes and natural killer cells. These results reveal a mechanical dimension of immunosurveillance, which we call mechanosurveillance, that is particularly relevant to the targeting of metastatic disease.

immunology↗