Delighted to share a terrific new study from a group of stellar fibrosis scientists at @Genentech. Congrats Ning Ding and team! cell.com/cell-metabolis…

Along with TurleyLab, Sören Müller, and our team Genentech, I'm thrilled to share our newest work out now in nature: nature.com/articles/s4158…. We show depleting TGFβ-driven LRRC15+ cancer-associated fibroblasts (CAFs) augments tumor control and response to immunotherapy🧵1/

Previous scRNAseq studies in cancer identified a predominant population of activated LRRC15+ myofibroblasts, that express high levels of immunosuppressive genes and associate with immunotherapy resistance. How LRRC15+ CAFs develop and function has remained unanswered 🤔2/

Using novel genetic tools, we show TGFβR2 signaling in healthy Dermatopontin (DPT)+ universal fibroblasts is essential for LRRC15+ CAF formation in mouse models of pancreatic cancer. These data validate prior in silico predictions that TGFβ is the key driver of these CAFs. 3/

Once LRRC15+ CAFs form, how do they impact tumor immunity? We made an LRRC15-DTR mouse to selectively ablate LRRC15+ CAFs from the TME🎯. Upon depletion, total tumor fibroblasts are diminished and tumor growth is significantly impaired. 4/

Kinetic scRNAseq of LRRC15+ CAF depleted tumors showed a recalibration of the tumor fibroblast compartment back towards a universal fibroblast-like state, highlighting the push and pull between universal fibs and LRRC15+ myofibroblasts in dictating tumor progression. 5/

Immunologically, depletion of CD8+ T cells in LRRC15+ CAF depleted tumors reversed the improved tumor control. Additional analysis of tumor CD8+ T cells, in the absence LRRC15+ CAFs, displayed enhanced effector function, indicating LRRC15+ CAF suppression of T cell activity. 6/

Imaging of tumors showing CD8s in close proximity to LRRC15+ CAFs further suggested cross-talk between these cells. And when co-cultured directly with LRRC15+ CAFs, CD8+ T cell functionality was suppressed, indicating LRRC15+ CAFs can directly limit their effector potential. 7/

Ultimately, this enabled us to ask if LRRC15+ CAFs limit response to immunotherapy. Here we find depletion of LRRC15+ CAFs markedly improved response to aPDL1 treatment, validating prior clinical associations between LRRC15+ CAFs and resistance to immune checkpoint blockade. 8/

Together, our findings tie together computational inferences, clinical associations, and now, in vivo validation, to support targeting of LRRC15+ CAFs to improve cancer immunotherapy💊. Such strategies may also be relevant in other diseases where similar myofibroblasts exist 9/

Most importantly, these exciting findings (and many more in the paper) were only possible b/c of the contributions of our incredible team of scientists. A big thank you 🙏🏾 to our co-authors and incredibly supportive community Genentech! There is still so much more to learn! /end

Feeling incredibly humbled and proud of this work with so many stellar trainees and long-standing collaborators! Giving special shout outs to co-corresponding author Sören Müller and lead author Akshay Krishnamurty. Here’s to teamwork and passion projects! trebuchet.public.springernature.app/get_content/ab…

Fibroblasts are key structural cells & some types are associated with cancer progression. In nature, Akshay Krishnamurty, Sören Müller, TurleyLab & team found that depleting a subset of these cells in tumors can improve responsiveness to cancer immunotherapy: go.nature.com/3RmlnJm

Targeting pathogenic CD4 #Tcells with CAR T cell therapy reverses the progression of multiple sclerosis-like disease in mice, finds new research from WashU Gregory Wu. 📄: scim.ag/7o

Terrific job opportunity with a stellar group leader focused on solving cutting-edge, B cell-related questions in human disease and drug development. The Yewdell Lab is a new addition to Immunology and Regenerative Medicine at Genentech. Join our community!

Did your lymph nodes swell after the Covid vaccine? That could be a good thing! Just hosted this pre-print of my final PhD project, investigating the multi-scale changes in lymph nodes after vaccination and how they relate to vaccine outcomes. biorxiv.org/content/10.110…

Beyond many others in the #MooneyLab, this was an exciting collaborative effort with TurleyLab at Genentech! Glad to start to share our findings!

Super fun celebrating a successful 2022 with TurleyLab and Sören Müller and our teams! Looking forward to a restful break and coming back in 2023 for fun, exciting, and collaborative science! Stroma, fibroblasts, and immunity FTW! #teamscienceisthebestscience

Adore this community beyond words! 💜 Happy Holidays everyone. Here’s to a year ahead teeming with curiosity, discovery and collaboration. x.com/akshayk25/stat…

Interested in restoring vision for people with AMD and other diseases of the retina? If so, then please check out this exciting new opportunity in ophthalmology research and drug development at Genentech! Join our stellar community. careers.gene.com/us/en/job/GENE…