Biology subjects

Odak, I.

Publications and source records attributed to Odak, I..

3 recordsLinked to original sources

bioRxiv2025

Potentiating CAR-T bystander killing by enhanced Fas/FasL signaling mitigates antigen escape in heterogeneous tumors

Antigen (Ag) escape is a frequent mechanism of relapse after CAR-T therapy, even though only [~]1% of leukemic and [~]0.1% of lymphoma cells are Ag- at baseline. In this study, we modeled extreme Ag heterogeneity (>20%) to define how Fas/FasL-dependent bystander killing contributes to tumor clearance. Across patient cohorts, Fas expression predicted survival after CD19 CAR-T therapy, particularly in CD19-low disease. In both murine and human systems, Fas-dependent bystander killing required Ag stimulation and cell contact, operated within a defined therapeutic window, and could eradicate large fractions of Ag- tumors in vivo. Pharmacologic potentiation with inhibitor of apoptosis protein antagonists or genetic stabilization of CAR-T membrane-bound FasL enhanced bystander killing but simultaneously induced CD4 T cell fratricide, which was rescued by CAR-T Fas knockout. Importantly, Fas sensitization also enabled bispecific antibody-redirected T cells to mediate bystander killing in resistant tumors. Finally, targeting tumor-associated macrophages triggered Fas-dependent clearance of neighboring tumor cells. These findings establish Fas-mediated bystander killing as a generalizable and therapeutically actionable axis to prevent Ag escape and broaden the scope of targeted T cell therapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/677496v1_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@11bedorg.highwire.dtl.DTLVardef@d09d07org.highwire.dtl.DTLVardef@1f53c1dorg.highwire.dtl.DTLVardef@13d96f9_HPS_FORMAT_FIGEXP M_FIG C_FIG Fas-mediated bystander killing can be potentiated by IAP inhibition and FasL stabilization, and further improved by decoupling CD4 T cell fratricide via Fas knockout. Schematic representation of CAR-T bystander killing across three mechanistic states. Left (Baseline): Antigen-positive (CD19) tumor cells activate CAR-T cells, leading to FasL-mediated cytotoxicity of neighboring antigen-negative (CD19-) tumor cells via membrane-bound FasL. Limited FasL expression and ADAM10-mediated shedding constrain bystander killing, and CD4 T cells are largely spared. Middle (Potentiated): Enhancing Fas signaling through IAP inhibition (IAPi), increasing FasL expression, and reducing FasL shedding result in improved bystander killing but also increased CD4 T cell fratricide. Right (Potentiated & Decoupled): Combining IAPi with FasL stabilization and CAR-T Fas knockout (FasKO) augments bystander killing while eliminating CD4 T cell fratricide.

immunology↗

bioRxiv2024

Integrative deep immune profiling of the elderly reveals systems-level signatures of aging, sex, smoking, and clinical traits

Elderly individuals have higher disease susceptibility and lower vaccine responsiveness, highlighting the need to better comprehend the aging immune system and its clinical associations. Here we conducted a deep immune profiling study of 550 elderly individuals (61-94 years) and 100 young adults (22-38 years). Utilizing high-dimensional spectral flow cytometry to identify 97 immune cell populations and 48-plex cytokine profiling, we detailed intricate age-and sex-related changes in the elderly immune system at an unprecedented depth. Synthesizing information from clinical, laboratory, and immunological data through an integrative multi-block analysis, we reveal overarching systems-level signatures of aging, such as increased concentrations of specific cytokines and frequencies of defined innate and adaptive immune cell subpopulations. Extending this approach, we identified unique immune signatures of smoking, obesity, and several diseases including osteoporosis, heart failure and gout. Our systems biology approach enables to uncover new relationships between clinical characteristics and immunological traits.

immunology↗

bioRxiv2020

A fetal wave of human type-3 γδ T cells with restricted TCR diversity persists into adulthood

Accumulating evidence suggests that the human embryonic thymus produces distinct waves of innate effector {gamma}{delta} T cells. However, it is unclear whether this process comprises a dedicated subset of IL-17-producing {gamma}{delta} T ({gamma}{delta}T17) cells, like reported in mice. Here we present a novel protocol for high-throughput paired {gamma}{delta} TCR-sequencing, which in combination with single-cell RNA-sequencing revealed a high heterogeneity of effector {gamma}{delta} T cell clusters. While immature {gamma}{delta} T cell clusters displayed mixed and diverse TCR, effector cell types in neonatal and adult blood segregated according to {gamma}{delta}TCR usage. In adult samples, mature V{delta}1+ T cells segregated into exhausted PD-1hi and active PD-1low clusters. Among V{gamma}9V{delta}2+ T cell subsets, we identified distinct PLZF-positive effector {gamma}{delta} T cell clusters with innate type-1 and type-3 T cell signatures that were already detectable in a public dataset of early embryonic thymus organogenesis. Together, this suggests that functionally distinct waves of human innate effector {gamma}{delta} T cells including CCR6+ {gamma}{delta}T17 cells develop in the early fetal thymus and persist into adulthood.

immunology↗