An intra-tumoral niche maintains and differentiates stem-like CD8 T cells

• Type of Material: Article
• Authors: Caroline S. Jansen, Emory University; Nataliya Prokhnevska, Emory University; Viraj Master, Emory University; Martin Sanda, Emory University; Jennifer Carlisle, Emory University; Mehmet Bilen, Emory University; Maria Cardenas, Emory University; Scott Wilkinson, National Cancer Institute; Ross Lake, National Cancer Institute; Adam G. Sowalsky, National Cancer Institute; Rajesh M. Valanparambil, Emory University; William Hudson, Emory University; Donald McGuire, Emory University; Kevin Melnick, Emory University; Amir L. Khan, Emory University; Kyu Kim, Emory University; Yun Min Chang, Emory University; Alice Kim, Emory University; Christopher Filson, Emory University; Mehrdad Alemozaffar, Emory University; Adeboye Osunkoya, Emory University; Patrick Mullane, Emory University; Carla Ellis, Emory University; Rama Akondy, Emory University; Sejin Im, Emory University; Alice O. Kamphorst, Icahn School of Medicine at Mount Sinai; Adriana Reyes, Emory University; Yuan Liu, Emory University; Haydn Kissick, Emory University
• Language: English
• Date: 2019-12-19
• Publisher: NATURE RESEARCH
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2019
• Final Published Version (URL): http://dx.doi.org/10.1038/s41586-019-1836-5
• Title of Journal or Parent Work: NATURE
• Volume: 576
• Issue: 7787
• Start Page: 465
• End Page: +
• Grant/Funding Information: This work was supported by funding from the Prostate Cancer Foundation, Swim Across America, the James M. Cox Foundation and James C. Kennedy, pilot funding from the Winship Cancer Institute supported by the Dunwoody Country Club Senior Men’s Association, and NCI grants 1-R00-CA197891 (H.K.) and U01-CA113913 (M.G.S.). We recognize Adaptive Biotechnologies for providing laboratory services as a part of an educational grant award. We would like to acknowledge the Yerkes NHP Genomics Core which is supported in part by NIH P51 OD011132, the Emory Flow Cytometry Core supported by the National Center for Georgia Clinical & Translational Science Alliance of the National Institutes of Health under award number UL1TR002378, the Intramural Research Program of the NIH, National Cancer Institute and the Emory University Integrated Cellular Imaging Microscopy Core of the Winship Cancer Institute of Emory University and NIH/NCI under award number 2P30CA138292-04.
• Keywords: SAFETY; PD-1 BLOCKADE; ANTI-PD-L1 ANTIBODY; SURVIVAL; RESPONSES; Science & Technology; TERTIARY LYMPHOID STRUCTURES; Multidisciplinary Sciences; Science & Technology - Other Topics; DENSITY; PREDICTOR
• Research Categories: Health Sciences, Oncology; Biology, Microbiology; Health Sciences, Immunology

Abstract

Tumour-infiltrating lymphocytes are associated with a survival benefit in several tumour types and with the response to immunotherapy1–8. However, the reason some tumours have high CD8 T cell infiltration while others do not remains unclear. Here we investigate the requirements for maintaining a CD8 T cell response against human cancer. We find that CD8 T cells within tumours consist of distinct populations of terminally differentiated and stem-like cells. On proliferation, stem-like CD8 T cells give rise to more terminally differentiated, effector-molecule-expressing daughter cells. For many T cells to infiltrate the tumour, it is critical that this effector differentiation process occur. In addition, we show that these stem-like T cells reside in dense antigen-presenting-cell niches within the tumour, and that tumours that fail to form these structures are not extensively infiltrated by T cells. Patients with progressive disease lack these immune niches, suggesting that niche breakdown may be a key mechanism of immune escape.