Rob Manguso, Associate Professor at Harvard Medical School and Massachusetts General Hospital, shared a post on X:
“Excited to share out latest work, out this week in Nature Genetics. In this study, we using CRISPR screens to explore how sensing inflammatory cytokines exposes new tumor-intrinsic dependencies.
We performed CRISPR screens across a range of 8 cancer models after exposure to IFNg, IFNb, and TNF, which are frequently produced at high levels by immune and host cells in the TME. The collection of 24 genome-scale screens reveals common and unique cytokine dependencies.
In general we find that cytokine-induced cancer dependencies are unique from those impacting growth in cell culture. They show some overlap with dependencies to ICB we identified using previous genome-wide in vivo screens, although many are in vivo-specific or cytokine-specific.
One interesting finding is that loss of the genes encoding for the subunits of the GPI-transamidase complex, which is necessary for GPI-anchoring of cell surface proteins, strongly sensitizes to cytokines, esp IFNb, and sensitizes tumors to ICB as well.
We also find an IFNg-specific dependency for loss of the lipid phosphatase FITM2, previously observed by Lawson et al. We found that deletion of this gene in tumors causes a dramatic sensitivity to immunotherapy in pancreatic and renal cancer models.
Much more great screening and mechanistic work in the manuscript. A tour de force by Collins Cheruiyot, a former HMS PhD student in my lab. Congratulations to Collins, Sarah Kim, Kathleen Yates, and all our co-authors and collaborators that made this work possible!”
Title: Inflammatory cytokines induce new cancer dependencies
Authors: Collins K. Cheruiyot, Sarah Y. Kim, Juan Dubrot, Sarah K. Lane-Reticker, Alex Miranda, Ashwin V. Kammula, Jonathan J. Perera, Peter P. Du, Cun Lan Chuong, Rachel A. Fetterman, Nelson H. Knudsen, Aiping Jiang, Juliette S. M. T. Suermondt, Lomax F. Pass, Cong Fu, Meng-Ju Wu, Lei Shi, Seth Anderson, Audrey J. Muscato, Omar I. Avila, Ian C. Kohnle, Emily A. Kessler, Hans W. Pope, Sarah G. Noel, Kira E. Olander, Jooho Chung, Kayla J. Colvin, Nabeel Bardeesy, Kathleen B. Yates, Robert T. Manguso
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