Biology subjects

Thommen, D. S.

Publications and source records attributed to Thommen, D. S..

4 recordsLinked to original sources

bioRxiv2025

Reinvigoration of translational activity in dysfunctional T cells initiates theearly intratumoral response to PD-1 blockade

T cells are key effectors of antitumor responses elicited by PD-1 blockade. However, it remains elusive by which mechanism(s) PD-1 blockade initiates T cell-driven antitumor immunity in cancer tissues. Here, we dissect early T cell reactivation upon anti-PD-1 in patient-derived tumor fragments. Using bispecific antibodies to target anti-PD-1 to individual T cell subsets, we demonstrate that intratumoral CD8+ and CD4+ T cells can independently drive immune remodeling of the tumor microenvironment. The CD8+ and CD4+ T cells that respond to anti- PD-1 exhibit a shared dysfunctional gene program, characterized by tumor-reactivity, terminal exhaustion, effector capacity, and reduced translational activity. Notably, rather than acting through transcriptional rewiring, anti-PD-1 reinvigorates dysfunctional T cells by overcoming this translational barrier, resulting in restored effector function. Altogether, these results reveal dysfunctional T cells as initiators of early tissue responses to PD-1 blockade and identify a novel mode of their therapeutic reinvigoration through restoration of translational control. One Sentence SummaryTranslational reactivation of tumor-residing dysfunctional T cells drives early intratumoral immune activity upon PD-1 blockade.

immunology↗

bioRxiv2025

MHC1-TIP enables single-tube multimodal immunopeptidome profiling and uncovers intratumoral heterogeneity in antigen presentation

Profiling antigens presented on MHC class I molecules on the cell surface is essential to identify candidate antigens for targeted and personalized immunotherapies. However, mass spectrometry-based immunopeptidomics has traditionally been limited by high input requirements, extensive sample manipulation, and expensive reagents. To overcome these challenges, we developed MHC1-TIP: a scalable, single-tube and cost-effective workflow to enable robust MHC-I ligandome recovery from cell lines, patient-derived organoids, and sub-milligram amounts of clinical tissues. Moreover, MHC1-TIP also preserves compatibility with additional omics profiling technologies and we demonstrate its capacity for quantitative and multimodal profiling of the proteome and immunopeptidome from the same sample to enable integrated analyses of protein expression and antigen presentation. Application of MHC1-TIP to primary renal cell carcinoma fragments revealed extensive intratumoral heterogeneity in antigen presentation that was poorly correlated with source protein expression. MHC1-TIP represents a broadly applicable and sensitive approach for low-input, multimodal immunopeptidomics with clinical and translational relevance.

systems biology↗

bioRxiv2021

Successful IL-12 cancer immunotherapy requires NK cell-derived CCL5 for anti-tumor DC-T cell crosstalk

T cell-directed cancer immunotherapy often fails to generate lasting tumor control. Harnessing additional effectors of the immune response against tumors may strengthen the clinical benefit of immunotherapies. Here, we demonstrate that therapeutic targeting of the IFN{gamma}-IL-12 pathway relies on the ability of a population of tissue-resident NK (trNK) cells to orchestrate an anti-tumor microenvironment. Particularly, utilizing an engineered adenoviral platform, we show that paracrine IL-12 enhances functional DC-CD8 T cell interactions to generate adaptive anti-tumor immunity. This effect depends on the abundance of trNK cells and specifically their capacity to produce the cDC1-chemoattractant CCL5. Failure to respond to IL-12 and other IFN{gamma}-inducing therapies such as immune checkpoint blockade in tumors with low trNK cell infiltration could be overcome by intra-tumoral delivery of CCL5. Our findings reveal a novel barrier for T cell-focused therapies and offer mechanistic insights into how T cell-NK cell-DC crosstalk can be enhanced to promote anti-tumor immunity and overcome resistance. SignificanceWe identified the lack of CCL5-producing, tissue-resident NK (trNK) cells as a barrier to T cell-focused therapies. While IL-12 induces anti-tumoral DC-T cell crosstalk in trNK cellrich tumors, resistance to IL-12 or anti-PD-1 in trNK cellpoor tumors can be overcome by the additional delivery of CCL5.

immunology↗

bioRxiv2020

Single Cell Analysis of Regions of Interest (SCARI) using a novel photoswitchable tag

The functional activity and differentiation potential of cells is determined by their interaction with surrounding cells. Approaches that allow the unbiased characterization of cell states while at the same time providing spatial information are of major value to assess this environmental influence. However, most current techniques are hampered by a trade-off between spatial resolution and cell profiling depth. Here, we developed a photoswitch-based technology that allows the isolation and in-depth analysis of live cells from regions of interest in complex ex vivo systems, including human tissues. The use of a highly sensitive 4-nitrophenyl(benzofuran)-cage coupled to nanobodies allowed photoswitching of cells in areas of interest with low-intensity violet light and without detectable phototoxicity. Single cell RNA sequencing of spatially defined CD8+ T cells was used to exemplify the feasibility of identifying location-dependent cell states at the single cell level. Finally, we demonstrate the efficient labeling and photoswitching of cells in live primary human tumor tissue. The technology described here provides a valuable tool for the analysis of spatially defined cells in diverse biological systems, including clinical samples.

bioengineering↗