Kavli Affiliate: Alexander Szalay
| Authors: Tricia R Cottrell, Jeffrey S Roskes, Michael Fotheringham, Emily Cohen, Boyang Zhang, Logan L Engle, Daphne Wang, Elizabeth Will, Joel C Sunshine, Daniel Jimenez-Sanchez, Zhen Zheng, Justina X Caushi, Jiajia Zhang, Nina D’Amiano, Julie Stein-Deutsch, Sonali Uttam, Katie Pirie, Darah Vlaminck, Michelle Mataj, Alexa Fiorante, Nicole Espinosa, Teodora Popa, Aleksandra Ogurtsova, Sigfredo Soto-Diaz, Margaret Eminizer, Sam Tabrisky, Andrew Jorquera, Jonathan Skidmore, Dmitry Medvedev, Jamie E Chaft, Julie R Brahmer, Michael Conroy, Joshua E Reuss, Ludmila Danilova, Hongkai Ji, Patrick M Forde, Drew M Pardoll, Kellie N Smith, Benjamin F Green, Alexander S Szalay and Janis M Taube
| Summary:
Probabilistic spatial modelling techniques developed on large-scale tumor-immune Atlases (∼35M individually mapped cells; 50,000 high power fields) were used to characterize predictive features of treatment-responsive lung cancer. We identified CD8+FoxP3+ cell density as a robust pre-treatment biomarker for outcomes across disease stages and therapy types. In parallel, single-cell RNAseq studies of CD8+FoxP3+ T-cells revealed an activated, early effector phenotype, substantiating an anti-tumor role, and contrasting with CD4+FoxP3+ T-regulatory cells. A spatial biomarker was developed using an empirical probabilistic model to define the immediate cell neighbors or niche surrounding CD8+FoxP3+ cells and proximity to the tumor-stromal boundary. The resultant ‘Diversity of Niches Unlocking Treatment Sensitivity (DONUTS)’ are more prevalent than the CD8+FoxP3+ cells themselves, mitigating sampling error in small biopsies. Further, the DONUTS only require four markers, are additive to PD-L1, and associate with tertiary lymphoid structure counts. Taken together, the DONUTS represent a next-generation predictive biomarker poised for clinical implementation. HIGHLIGHTS Large-scale tumor-immune Atlases drive robust computational biomarker development CD8+FoxP3+ cells are anti-tumor T-cells and predict response to therapy The niches or spatial ‘donuts’ around CD8+FoxP3+ cells boost biomarker performance CD8+FoxP3+ donuts are hallmarks of a larger immune organization that includes TLS