Biology subjects

Latifi, L.

Publications and source records attributed to Latifi, L..

3 recordsLinked to original sources

bioRxiv2026

Systemic viral vector vaccination induces brain resident memory T cells to drive anti-glioblastoma immunity

Glioblastoma is a lethal brain tumor that is unresponsive to current cancer immunotherapeutic approaches, including immune checkpoint blockade (ICB). This suggests that initial priming of T cells, rather than their expansion and licensing as effectors, is a restricting feature in this tumor setting. To overcome the limited initiation of CD8+ T cell responses, we employed a strong heterologous prime-boost vaccination with the simian adenovirus ChAdOx1 and poxvirus modified vaccinia Ankara (MVA). Vaccination conferred therapeutic efficacy against orthotopic, immune checkpoint-blockade (ICB)-refractory SB28 murine glioblastoma. Vaccination was effective against both the murine tumor antigen, P1A, and a newly identified glioblastoma-associated antigen, Gpr149. Additional treatment with ICB provided no additional benefit. Systemic ChAdOx1/MVA vaccination induced robust infiltration of antigen-specific T cells in tumor-challenged brains, the majority of which exhibited a CD103+CD69+CD8+ tissue-resident memory (TRM)-like phenotype. These cells were polyfunctional, durable in brains with sustained tumor control, and mediated tissue-specific immunological memory. Moreover, intracranial adoptive transfer of glioblastoma-derived antigen-specific TRM-like cells was sufficient to protect naive recipients from subsequent orthotopic tumor challenge. Together, these findings establish that viral vector vaccination can generate tumor-specific TRM-like cells that mediate effective anti-glioblastoma immunity, providing a rationale for clinical evaluation of ChAdOx1/MVA-based strategies in glioblastoma.

immunology↗

bioRxiv2025

FGF-dependent, polarized SOS activity orchestrates directed migration of C. elegans muscle progenitors independently of canonical effectors in vivo

Directed cell migration is essential for animal development, tissue maintenance, regeneration, and disease states. Cells often migrate towards, or away from, sources of secreted signaling proteins that impart spatial information. How migrating cells interpret extracellular signals to orient and navigate within living animals is a fundamental question in biology. Receptor Tyrosine Kinase (RTK) signaling plays critical roles in cell migration, and aberrant RTK pathway activity is a key driver of multiple types of cancers. Yet, how RTKs control cell migration in living animals remains unclear, in part due to essential, pleiotropic roles of key proteins in development. To elucidate how RTK signaling controls cell migration in vivo, we dissected spatial and temporal requirements for key signal transduction and cytoskeletal regulatory proteins using C. elegans muscle progenitor migration as a tractable model. Cell type-specific depletion of endogenously tagged proteins revealed that homologs of FGFR, GRB2, SOS, and Ras control cell migration independently of their canonical ERK, PI3K, Akt, mTOR, and PLC{psi} effectors. Instead, we found that FGF-dependent, polarized SOS-1 orients migrating cells towards an FGF source, and mislocalizing SOS activity within migrating cells severely disrupts migration independent of ERK. Cell type-specific, gain-of-function experiments demonstrated that activated Ras is largely permissive for anterior migration in this context, and an intragenic revertant identified in a screen for suppressors of activated Ras/let-60 revealed that signal transduction in migrating muscle progenitors can be genetically uncoupled from Ras-ERK-dependent developmental processes. We found that conserved regulators of branched actin assembly control SM protrusive dynamics but are not essential for accurate, FGF-directed migration. Our findings provide a novel mechanism for RTK-directed cell migration in vivo and highlight the importance of cell type-specific approaches to elucidate signal transduction mechanisms in physiologically relevant contexts. Our work also outlines a comprehensive framework for investigating RTK-dependent processes in a multicellular organism and introduces a versatile genetic toolkit for dissecting spatial and temporal signaling dynamics fundamental to development, homeostasis, and disease.

cell biology↗

bioRxiv2023

A simple method to dramatically increase C. elegans germline microinjection efficiency

Genome manipulation methods in C. elegans require microinjecting DNA or ribonucleoprotein complexes into the microscopic core of the gonadal syncytium. These microinjections are technically demanding and represent a key bottleneck for all genome engineering and transgenic approaches in C. elegans. While there have been steady improvements in the ease and efficiency of genetic methods for C. elegans genome manipulation, there have not been comparable advances in the physical process of microinjection. Here, we report a simple and inexpensive method for handling worms using a paintbrush during the injection process that nearly tripled average microinjection rates compared to traditional worm handling methods. We found that the paintbrush increased injection throughput by substantially increasing both injection speeds and post-injection survival rates. In addition to dramatically and universally increasing injection efficiency for experienced personnel, the paintbrush method also significantly improved the abilities of novice investigators to perform key steps in the microinjection process. We expect that this method will benefit the C. elegans community by increasing the speed at which new strains can be generated and will also make microinjection-based approaches less challenging and more accessible to personnel and labs without extensive experience.

genetics↗