Biology subjects

Sheffer, M.

Publications and source records attributed to Sheffer, M..

3 recordsLinked to original sources

bioRxiv2026

Tumor-tropic E. coli engineered as living T and NK cell engagers

Despite advances in immunotherapy, most solid tumors remain resistant to treatment. Immune cell engagers redirect cytotoxic lymphocytes against cancer, but limited tumor access, immunosuppressive microenvironments and systemic immune activation limit efficacy. Here we develop live immune modulating engagers (LIME), a modular platform where non-pathogenic, tumor-tropic Escherichia coli display tandem single-chain variable fragments targeting a tumor-associated antigen and an activating receptor on T or natural killer cells. LIME bridged effector and tumor cells, induced transcriptional programs of T cell activation, metabolism and proliferation, and enhanced cytotoxicity across cancer cell lines and patient-derived organoids. In mouse models, LIME safely accumulated in tumors, outperformed tarlatamab in small cell lung cancer, and induced durable immunity in lymphoma. RAS inhibition and PD-L1 blockade enhanced LIME activity in pancreatic cancer and induced humoral responses. Multi-lineage immune modulation remained tumor-confined, without organ toxicity. These findings establish LIME as a versatile living therapeutic platform for programmable, tumor-restricted immune orchestration.

bioengineering↗

bioRxiv2024

Insect size responses to climate changes vary across elevations according to seasonal timing

Widespread plastic and evolutionary responses to temperature have led to body size declines being proposed as a universal response to warming, but the high degree of variation in terrestrial ectotherms has challenged this view. We investigate whether temperature dependent development and growth rates in ectothermic organisms drive departures from universal size responses. Leveraging a long-term study of montane grasshoppers, we detect size shifts over recent decades that depend on elevation and species seasonal timing. Size shifts have been focused at low elevations with the earliest emerging species (those that overwinter as juveniles) getting bigger, and later season species getting smaller. The shifts correspond to warmer temperatures at low elevation increasing the sizes of the earliest season species but decreasing the sizes of the later season species. This is consistent with our hypothesis that the earliest season species may be able to take advantage of warmer conditions accelerating growth during early spring development, whereas warm temperatures may adversely impact later season species via mechanisms such as increased rates of energy use or thermal stress. Grasshoppers tend to capitalize on warm conditions by both getting bigger and reaching adulthood earlier. Our analysis further reinforces the need to move beyond expectations of universal responses to climate change to consider how environmental exposure and sensitivity varies across elevations and life histories.

ecology↗

bioRxiv2022

Single-cell functional genomics of natural killer cell evasion in blood cancers

Natural killer (NK) cells are emerging as a promising therapeutic option in cancer. To better understand how cancer cells evade NK cells, we studied interacting NK and blood cancer cells using single-cell and genome-scale functional genomics screens. At single-cell resolution, interaction of NK and cancer cells induced distinct activation states in both cell types depending on the cancer cell lineage and molecular phenotype, ranging from more sensitive myeloid to more resistant B-lymphoid cancers. CRISPR screens uncovered cancer cell-intrinsic genes driving sensitivity and resistance, including antigen presentation and death receptor signaling mediators, adhesion molecules, protein fucosylation genes, and transcriptional regulators. CRISPR screens with a single-cell transcriptomic readout revealed how these cancer cell genes influenced the gene expression landscape of both cell types, including regulation of activation states in both cancer and NK cells by IFN{gamma} signaling. Our findings provide a resource for rational design of NK cell-based therapies in blood cancers. HIGHLIGHTSO_LITranscriptomic states of interacting NK cells and cancer cells depend on cancer cell lineage C_LIO_LIMolecular correlates of increased sensitivity of myeloid compared to B-lymphoid cancers include activating receptor ligands NCR3LG1, PVR, and ULBP1 C_LIO_LINew regulators of NK cell resistance from 12 genome-scale CRISPR screens include blood cancer-specific regulators SELPLG, SPN, and MYB C_LIO_LISingle-cell transcriptomics CRISPR screens targeting 65 genome-wide screen hits identify MHC-I, IFNy, and NF-{kappa}B regulation as underlying mechanisms C_LI

immunology↗