TY - JOUR
T1 - B cells and tertiary lymphoid structures promote immunotherapy response
AU - Helmink, Beth A.
AU - Reddy, Sangeetha M.
AU - Gao, Jianjun
AU - Zhang, Shaojun
AU - Basar, Rafet
AU - Thakur, Rohit
AU - Yizhak, Keren
AU - Sade-Feldman, Moshe
AU - Blando, Jorge
AU - Han, Guangchun
AU - Gopalakrishnan, Vancheswaran
AU - Xi, Yuanxin
AU - Zhao, Hao
AU - Amaria, Rodabe N.
AU - Tawbi, Hussein A.
AU - Cogdill, Alex P.
AU - Liu, Wenbin
AU - LeBleu, Valerie S.
AU - Kugeratski, Fernanda G.
AU - Patel, Sapna
AU - Davies, Michael A.
AU - Hwu, Patrick
AU - Lee, Jeffrey E.
AU - Gershenwald, Jeffrey E.
AU - Lucci, Anthony
AU - Arora, Reetakshi
AU - Woodman, Scott
AU - Keung, Emily Z.
AU - Gaudreau, Pierre Olivier
AU - Reuben, Alexandre
AU - Spencer, Christine N.
AU - Burton, Elizabeth M.
AU - Haydu, Lauren E.
AU - Lazar, Alexander J.
AU - Zapassodi, Roberta
AU - Hudgens, Courtney W.
AU - Ledesma, Deborah A.
AU - Ong, Su Fey
AU - Bailey, Michael
AU - Warren, Sarah
AU - Rao, Disha
AU - Krijgsman, Oscar
AU - Rozeman, Elisa A.
AU - Peeper, Daniel
AU - Blank, Christian U.
AU - Schumacher, Ton N.
AU - Butterfield, Lisa H.
AU - Zelazowska, Monika A.
AU - McBride, Kevin M.
AU - Kalluri, Raghu
AU - Allison, James
AU - Petitprez, Florent
AU - Fridman, Wolf Herman
AU - Sautès-Fridman, Catherine
AU - Hacohen, Nir
AU - Rezvani, Katayoun
AU - Sharma, Padmanee
AU - Tetzlaff, Michael T.
AU - Wang, Linghua
AU - Wargo, Jennifer A.
N1 - Funding Information:
Acknowledgements The correlative research was funded by philanthropic support from the MD Anderson Melanoma Moon Shot Program, the Parker Institute for Cancer Immunotherapy, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the AIM at Melanoma Foundation. It was supported by The Immunotherapy Platform and the Core grant CA016672 (SMF) to support the Sequencing and Microarray Facility at UT-MDACC as well as the the Office of the Assistant Secretary for Defense for Health Affairs grant (W81XWH-16-1-0120 and W81XWH-16-1-0121). S.M.R. received support from National Institutes of Health T32 CA 009666 and Cancer Prevention Research Institute of Texas RR190020. B.A.H. received support from National Institutes of Health T32 CA 009599 and the MD Anderson Cancer Center support grant P30 CA016672. A.P.C. is supported by the CPRIT Research Training Program (RP170067) and the United States Department of State’s Bureau of Educational and Cultural Affairs. E.Z.K. is supported by National Institutes of Health grant T32 CA009599. F.G.K. is supported with funding from the Odyssey Program at the MD Anderson Cancer Center with support from the Theodore N. Law Endowment for Scientific Achievement. Research in the Kalluri laboratory is supported by the Cancer Prevention and Research Institute of Texas and National Cancer Institute grants CA213233, P01CA117969, and CA195733. K.M.M. and M.A.Z. are supported by CPRIT RP190507. The High Resolution Electron Microscopy Facility at UT-MDASS is supported by CCSG grant NIGH P30CA016672. We thank to O. Contrares for technical support on the multiplex immunofluorescence and for M. Andrews for technical support on RNA-seq library preparation and K. McAndrews, D. P. Dowlatshahi, L. Snowden, J. Leveille and S. Yang for support with analyses of exosomes.
Funding Information:
Competing interests J.A.W. is an inventor on a US patent application (PCT/US17/53.717) submitted by the University of Texas MD Anderson Cancer Center that covers methods to enhance immune checkpoint blockade responses by modulating the microbiome. J.A.W. reports compensation for speaker’s bureau and honoraria from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, Physician Education Resource, MedImmune and Bristol-Myers Squibb. J.A.W. serves as a consultant/advisory board member for Roche/Genentech, Novartis, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Merck, Biothera Pharmaceuticals and Microbiome DX. J.A.W. also receives research support from GlaxoSmithKline, Roche/Genentech, Bristol-Myers Squibb, and Novartis. J.A.W., S.M.R. and B.A.H. are co-inventors on an unpublished patent application related to methods of targeting B cells to enhance response to immune checkpoint blockade. M.T.T. reports advisory board participation and speaker paid honorarium from Nanostring and Myriad Genetics. M.A.D. serves as a paid consultant for BMS, Novartis, and Roche/Genentech. M.A.D. also reports to be a principal investigator of a research grant from Roche/Genentech and an unpaid consultant to Nanostring. C.U.B. reports an advisory role in BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, GenMab and Pierre Fabre. C.U.B. receives research funding from BMS, Novartis and Nanostring. C.U.B. reports stock ownership from Uniti Cars and Neon Therapeutics. N.H. is a founder, stockholder and SAB member of Neon Therapeutics. W.H.F. serves as a consultant for AstraZeneca, Ipsen, Adaptimmune, OxfordBiotherapeutics, and Catalym. W.H.F. reports participation in data transparency committee for Servier and data management committee for Novartis. O.K. receives grant support from BMS. J.E.G. is a contributor of UpToDate-melanoma staging and prognosis. J.E.G. reports to be an unpaid member of Melanoma Research Foundation and Melanoma Research Alliance. J.E.G. reports to be on advisory board of Merck. R.K. reports to be scientific founder, stockholder and consultant of Codiak Biosciences. A.J.L. reports consultancies and research support from BMS, Genentech/Roche and MedImmune/ Astra-Zeneca. P.S. reports a patent licensed to Jounce Therapeutics. P.S. serves as a consultant for Constellation, Jounce Therapeutics, Neon, BioAtla, Pieris, Oncolytics, Forty-Seven, Polaris, Apricity, Marker, Codiak, ImaginAb, Hummingbird, Dragonfly, Lytix and Bristol-Myers Squibb (BMS). P.S. has ownership interests in Jounce Therapeutics, Neon, Constellation, Oncolytics, BioAtla, Forty-Seven, Apricity, Polaris, Marker, Codiak, ImaginAb, Hummingbird, Dragonfly and Lytix. L.H.B. reports to be on StemImmune/Calidi Scientific and Medical Advisory, Scientific Advisory Board of BoardNextCure, Replimmune, Western Oncolytics, Torque Therapeutics Khloris, Pyxis, Cytomix. L.H.B. reports to be Chair of Food and Drug Administration Cellular, Tissues and Gene Therapies Advisory Committee. R.Z. reports a patent application related to work on GITR, PD1 and CTLA4. R.Z. is a consultant for Leap Therapeutics. P.H. is on advisory board for Dragonfly, GlaxoSmithKline, Immatics and Sanofi. S.W., S.O. and M.B. are employees and stockholders of NanoString Technologies. All other authors report no competing interests directly relevant to this work.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/1/23
Y1 - 2020/1/23
N2 - Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1–10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11–15, although these have been less well-studied in ICB treatment16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter18) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.
AB - Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1–10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11–15, although these have been less well-studied in ICB treatment16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter18) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.
UR - http://www.scopus.com/inward/record.url?scp=85078126241&partnerID=8YFLogxK
U2 - 10.1038/s41586-019-1922-8
DO - 10.1038/s41586-019-1922-8
M3 - Article
C2 - 31942075
AN - SCOPUS:85078126241
SN - 0028-0836
VL - 577
SP - 549
EP - 555
JO - Nature
JF - Nature
IS - 7791
ER -