TY - JOUR
T1 - An activation to memory differentiation trajectory of tumor-infiltrating lymphocytes informs metastatic melanoma outcomes
AU - Jaiswal, Abhinav
AU - Verma, Akanksha
AU - Dannenfelser, Ruth
AU - Melssen, Marit
AU - Tirosh, Itay
AU - Izar, Benjamin
AU - Kim, Tae Gyun
AU - Nirschl, Christopher J.
AU - Devi, K. Sanjana P.
AU - Olson, Walter C.
AU - Slingluff, Craig L.
AU - Engelhard, Victor H.
AU - Garraway, Levi
AU - Regev, Aviv
AU - Minkis, Kira
AU - Yoon, Charles H.
AU - Troyanskaya, Olga
AU - Elemento, Olivier
AU - Suárez-Fariñas, Mayte
AU - Anandasabapathy, Niroshana
N1 - Funding Information:
This work was supported by NCI K08CA222663, R21CA263381, and R37CA258829, a Career Award for Medical Scientists from the Burroughs Wellcome Fund (to B.I.), a Clinic and Laboratory Integration Program (CLIP) award from the Cancer Research Institute (to C.L.S.), PHS grant R21CA185955 (to V.H.E.), and an NCI P30 CA44579 to the University of Virginia Cancer Center. S.D. was supported in part by a fellowship from SunPharma. C.N. was supported by 5T32AR007098 Dermatology Training Grant. Support for N.A. is from the National Institute of Arthritis and Musculoskeletal and Skin Disease R01 AR070234, AR080436, R56 AR078686-01, Sun Pharma award 5327097901, and WCMC (to N.A.). Conceptualization, N.A. M.S.-F. O.T. O.E. A.J. A.V. and I.T.; methodology, N.A. M.S.-F. A.J. A.V. O.T. O.E. A.R. L.G. and B.I.; software, A.J. A.V. M.S.-F. R.D. I.T. O.E. and O.T.; investigation, A.J. N.A. M.S.-F. A.V. O.E. R.D. O.T. M.M. I.T. T.-G.K, C.J.N. K.P.D. C.L.S. W.C.O. V.H.E. and B.I.; resources, N.A. M.S.-F. A.R. C.H.Y. L.G. W.C.O. C.L.S. O.T. O.E. K.M. and B.I.; supervision, N.A. M.S.-F. O.E. O.T. C.L.S. V.H.E. and A.R.; funding acquisition, N.A. O.E. O.T. L.G. and A.R.; writing, A.J. N.A. M.S.-F. A.V. R.D. and I.T. N.A. is a scientific advisor and an equity holder in Shennon Biotechnologies, and is a consultant for Janssen, Immunitas, and Cellino Pharmaceuticals. B.I. is a consultant for Volastra Therapeutics Inc. Johnson & Johnson/Janssen, and received honoraria from AstraZeneca and Merck. None of these represent a conflict of interest pertaining to the presented work. O.E. is supported by Janssen, Johnson & Johnson, Astra-Zeneca, Volastra, and Eli Lilly research grants. He is scientific advisor to and equity holder in Freenome, Owkin, Volastra Therapeutics, Harmonic Discovery, and OneThree Bio, and a paid scientific advisor to Champions Oncology and Pionyr Therapeutics. O.T. is on the Scientific Advisory Board of Caris Life Sciences. V.H.E. is a consultant and shareholder for Agenus, Inc. A.R. is a founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics and, until August 31, 2020, was a SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov, and Thermo Fisher Scientific. From August 1, 2020, A.R. is an employee of Genentech, a member of the Roche Group. A.R. is an inventor on multiple patents related to single-cell and spatial genomics filed by the Broad Institute. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as living with a disability. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list.
Funding Information:
This work was supported by NCI K08CA222663 , R21CA263381 , and R37CA258829 , a Career Award for Medical Scientists from the Burroughs Wellcome Fund (to B.I.), a Clinic and Laboratory Integration Program ( CLIP ) award from the Cancer Research Institute (to C.L.S.), PHS grant R21CA185955 (to V.H.E.), and an NCI P30 CA44579 to the University of Virginia Cancer Center . S.D. was supported in part by a fellowship from SunPharma. C.N. was supported by 5T32AR007098 Dermatology Training Grant. Support for N.A. is from the National Institute of Arthritis and Musculoskeletal and Skin Disease R01 AR070234 , AR080436 , R56 AR078686-01 , Sun Pharma award 5327097901 , and WCMC (to N.A.).
Funding Information:
N.A. is a scientific advisor and an equity holder in Shennon Biotechnologies, and is a consultant for Janssen, Immunitas, and Cellino Pharmaceuticals. B.I. is a consultant for Volastra Therapeutics Inc., Johnson & Johnson/Janssen, and received honoraria from AstraZeneca and Merck. None of these represent a conflict of interest pertaining to the presented work. O.E. is supported by Janssen, Johnson & Johnson, Astra-Zeneca, Volastra, and Eli Lilly research grants. He is scientific advisor to and equity holder in Freenome, Owkin, Volastra Therapeutics, Harmonic Discovery, and OneThree Bio, and a paid scientific advisor to Champions Oncology and Pionyr Therapeutics. O.T. is on the Scientific Advisory Board of Caris Life Sciences. V.H.E. is a consultant and shareholder for Agenus, Inc. A.R. is a founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics and, until August 31, 2020, was a SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov, and Thermo Fisher Scientific. From August 1, 2020, A.R. is an employee of Genentech, a member of the Roche Group. A.R. is an inventor on multiple patents related to single-cell and spatial genomics filed by the Broad Institute.
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/5/9
Y1 - 2022/5/9
N2 - There is a need for better classification and understanding of tumor-infiltrating lymphocytes (TILs). Here, we applied advanced functional genomics to interrogate 9,000 human tumors and multiple single-cell sequencing sets using benchmarked T cell states, comprehensive T cell differentiation trajectories, human and mouse vaccine responses, and other human TILs. Compared with other T cell states, enrichment of T memory/resident memory programs was observed across solid tumors. Trajectory analysis of single-cell melanoma CD8+ TILs also identified a high fraction of memory/resident memory-scoring TILs in anti-PD-1 responders, which expanded post therapy. In contrast, TILs scoring highly for early T cell activation, but not exhaustion, associated with non-response. Late/persistent, but not early activation signatures, prognosticate melanoma survival, and co-express with dendritic cell and IFN-γ response programs. These data identify an activation-like state associated to poor response and suggest successful memory conversion, above resuscitation of exhaustion, is an under-appreciated aspect of successful anti-tumoral immunity.
AB - There is a need for better classification and understanding of tumor-infiltrating lymphocytes (TILs). Here, we applied advanced functional genomics to interrogate 9,000 human tumors and multiple single-cell sequencing sets using benchmarked T cell states, comprehensive T cell differentiation trajectories, human and mouse vaccine responses, and other human TILs. Compared with other T cell states, enrichment of T memory/resident memory programs was observed across solid tumors. Trajectory analysis of single-cell melanoma CD8+ TILs also identified a high fraction of memory/resident memory-scoring TILs in anti-PD-1 responders, which expanded post therapy. In contrast, TILs scoring highly for early T cell activation, but not exhaustion, associated with non-response. Late/persistent, but not early activation signatures, prognosticate melanoma survival, and co-express with dendritic cell and IFN-γ response programs. These data identify an activation-like state associated to poor response and suggest successful memory conversion, above resuscitation of exhaustion, is an under-appreciated aspect of successful anti-tumoral immunity.
KW - ICB
KW - T cell memory
KW - TILs
KW - immune checkpoint blockade
KW - immune persistence
KW - melanoma
KW - survival
KW - systems biology
KW - tumor-infiltrating lymphocytes
UR - http://www.scopus.com/inward/record.url?scp=85129661765&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85129661765&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2022.04.005
DO - 10.1016/j.ccell.2022.04.005
M3 - Article
C2 - 35537413
AN - SCOPUS:85129661765
SN - 1535-6108
VL - 40
SP - 524-544.e5
JO - Cancer Cell
JF - Cancer Cell
IS - 5
ER -