Biology subjects

Hirdler, J. B.

Publications and source records attributed to Hirdler, J. B..

4 recordsLinked to original sources

bioRxiv2025

PD-1 prelimits both the cytotoxic and exhaustion potential in thymic CD8+ T cells and impacts the maintenance of peripheral tumor immunity

Durable T cell immunity against cancer depends on the continual replenishment of effector CD8+ T cells. Thymic output has been correlated with favorable prognosis in cancer patients across a range of ages, suggesting that the thymus is an important source for replenishing T cells capable of controlling cancer progression. However, the effector potential of thymic mature CD8+ T cells and their regulation have not been clearly defined. In this study, we identified the ability of thymic single positive CD8+ T cells to gain effector potential after thymic selection, but they are subject to the regulation of PD-1. We found a previously undisclosed role of PD-1 in limiting both the cytotoxic and exhaustion potential of thymic and peripheral CD8+ T cells. Our results show that although PD-1 inhibition facilitates the expansion of effector CD8+ T cells, effector CD8+ cells gradually lose their antitumor activity within tumor tissues due to advanced exhaustion in the absence of PD-1. Thus, although the preset effector potential in thymic mature CD8+ T cells allows them to rapidly respond to malignant cells in the periphery, PD-1, as a checkpoint, is embedded in the thymic mature CD8+ T cells after positive selection to balance their effector function from exaggeration and exhaustion. Therefore, we propose that a strategy capable of upholding the cytotoxic capacity and avoiding exhaustion of CD8+ T cells during the early stages of PD-1 inhibition therapy is needed to achieve durable antitumor immunity.

immunology↗

bioRxiv2024

Single CAR-Dual target: Intracranial Delivery of Anti-PD-L1 CAR T Cells Effectively Eradicates Glioma and Immunosuppressive Cells in the Tumor Microenvironment.

With the goal to overcome the limited treatment options and poor prognosis of glioblastoma (GBM), we have developed a PD-L1-targeting CAR T cell therapy, MC9999. In vitro experiments with MC9999 CAR T cells derived from GBM patients exhibited potent, antigen-specific cytotoxicity against autologous tumor cells and immunosuppressive cells within the tumor microenvironment (TME). In an orthotopic GBM model using patient-derived brain tumor-initiating cells, the intracranial delivery of MC9999 CAR T cells eradicated established tumors and improved survival. Single-cell RNA sequencing indicated that MC9999 CAR T cells activate interferon pathways, leading to GBM cell apoptosis. Multi-immunohistochemistry confirmed localized PD-L1 expression on tumor cells and TME-residing macrophages, but not in neurons or glia in patient tissue. The local delivery of MC9999 CAR T cells may be a safe, effective approach for simultaneously targeting PD-L1-positive GBM and its immunosuppressive TME and a strategy to overcome immune evasion and enhance the therapeutic potency of CAR T cell therapy against GBM.

cancer biology↗

bioRxiv2022

Resilient CD8+ T cells maintain a high cytotoxic capacity by balancing ROS via ME1 upregulation

Cytotoxic T lymphocytes (CTL) are indispensable in anti-tumor immunity. Although CTLs are prone to exhaustion in patients with advanced cancer, T cell resiliency explains the presence of tumor-reactive CTLs that are less exhausted, capable of cytolytic function, expansion, and rebound in response to immunotherapy to reject metastatic malignances. However, the features of resilient T cells have not been clearly defined. In this report, we demonstrate that peripheral CX3CR1+ CD8+ T cells with low mitochondrial membrane potential rebounded CTL function quickly after radiation therapy in patients with large tumor burden portraying their functional resiliency. Furthermore, CX3CR1+ CD8+ T cell with low, but not high, mitochondrial membrane potential are highly cytotoxic, accumulate less reactive oxygen species (ROS), and express more Malic enzyme 1 (ME1). ME1 overexpression increases ATP production in a glycolysisindependent manner while concurrently curtailing excessive ROS in activated CD8+ T cells; and expands CX3CR1+NKG7+ effector CD8+ T cells with enhanced cytotoxicity. Importantly, transfection of ME1 mRNA promotes tumoricidal activity in CD8+ T cells from patients with advanced cancers. Our study reveals a mechanism used by CTLs to balance excessive ROS via ME1 to maintain a metabolic and functional resiliency. Modification of ME1 expression in CTLs may be a novel method to improve the efficacy of cancer immunotherapy by preventing T cell exhaustion. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=191 SRC="FIGDIR/small/517988v3_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@12e0f36org.highwire.dtl.DTLVardef@e8d412org.highwire.dtl.DTLVardef@1baf57eorg.highwire.dtl.DTLVardef@14b2b43_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LICX3CR1+ and low Dy m identify functional resilient CD8+ T cells. C_LIO_LIResilient CD8+ T cells are highly cytotoxic and have less ROS. C_LIO_LIResilient CD8+ T cells express more ME1 that can balance extra ROS. C_LIO_LIME1 overexpression can promote CTL function of CD8+ T cells. C_LI

immunology↗

bioRxiv2022

Discovery of a novel monoclonal PD-L1 antibody H1A that promotes T-cell mediated tumor killing activity in renal cell carcinoma

In the last decade, the therapeutic landscape of renal cell carcinoma has rapidly evolved with the addition of PD-1/PD-L1 immune checkpoint inhibitors in the armamentarium of oncologists. Despite clinical evidence of improved oncological outcomes, only a minority of patients experience long-lasting antitumor immune response and complete response. The intrinsic and acquired resistance to PD-1/PD-L1 immune checkpoint blockade is an important challenge for patients and clinicians as no reliable tool has been developed to predict individualized response to immunotherapy. In this study, we demonstrate the translational relevance of an ex-vivo functional assay that measure the tumor cell killing ability of patient-derived CD8 T cells isolated from peripheral blood. Cytotoxic activity of CD8 T cells was improved at 3-month post-radical nephrectomy compared to baseline and it was associated with higher circulating levels of tumor-reactive effector CD8 T cells (CD11ahighCX3CR1+GZMB+). Pretreatment of peripheral immune cells with FDA-approved PD-1/PD-L1 inhibitors enhanced tumor cell killing activity of CD8 T cells but differential response was observed at the individual patient level. Finally, we found a newly developed monoclonal antibody (H1A), which induces PD-L1 degradation, demonstrated superior efficacy in promoting T-cell mediated tumor killing activity compared to FDA-approved PD-1/PD-L1 inhibitors. PBMC immunophenotyping by mass cytometry revealed enrichment of effector CD8 T cells in H1A-treated PBMC. To conclude, our study lays the ground for future investigation of the therapeutic value of H1A as a next-generation immune checkpoint inhibitor. Furthermore, further work is needed to evaluate the potential of measuring T-cell cytotoxicity activity as a tool to predict individual response to immune checkpoint inhibitors in patients with advanced renal cell carcinoma.

immunology↗