TY - JOUR
T1 - Melanoma evolves complete immunotherapy resistance through the acquisition of a hypermetabolic phenotype
AU - Jaiswal, Ashvin R.
AU - Liu, Arthur J.
AU - Pudakalakatti, Shivanand
AU - Dutta, Prasanta
AU - Jayaprakash, Priyamvada
AU - Bartkowiak, Todd
AU - Ager, Casey R.
AU - Wang, Zhi Qiang
AU - Reuben, Alexandre
AU - Cooper, Zachary A.
AU - Ivan, Cristina
AU - Ju, Zhenlin
AU - Nwajei, Felix
AU - Wang, Jing
AU - Davies, Michael A.
AU - Eric Davis, R.
AU - Wargo, Jennifer A.
AU - Bhattacharya, Pratip K.
AU - Hong, David S.
AU - Curran, Michael A.
N1 - Funding Information:
A.R. Jaiswal reports current affiliation with MedImmune/AstraZeneca (the study was conducted at MD Anderson prior to A.R. Jaiswal joining MedImmune/ AstraZeneca). Z.A. Cooper reports other from AstraZeneca (current employee and stock) outside the submitted work. M.A. Davies reports personal fees from Bristol-Myers Squibb (consultant), Novartis (consultant), Apexigen (consultant), and Array (consultant); grants and personal fees from Roche/Genentech (consultant; principal investigator of grant to institution) and GlaxoSmithKline (consultant; principal investigator of grant to institution); grants from AstraZeneca (principal investigator of grant to institution); and personal fees from Vaccinex (consultant) outside the submitted work. J.A. Wargo reports grants from GlaxoSmithKline, Roche/ Genentech, Bristol-Myers Squibb, grants and personal fees from AstraZeneca and Merck, and personal fees from PeerView and Physician Education Resource outside the submitted work, as well as a patent for PCT/US17/53.717 pending to MD Anderson. D.S. Hong reports for the past 36 months research/grant funding from AbbVie, Adaptimmune, Aldi-Norte, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, miRNA, Molecular Templates, Mologen, NCI-Cancer Therapy Evaluation Program (CTEP), Novartis, Pfizer, Seattle Genetics, Takeda, and Turning Point Therapeutics; travel, accommodations, and expenses from Bayer, LOXO, miRNA, Genmab, AACR, American Society of Clinical Oncology (ASCO), and Society for Immunotherapy of Cancer (SITC); consulting/advisory roles with Alpha Insights, Acuta, Amgen, Axiom, Adaptimmune, Baxter, Bayer, COG, Ecor1, Genentech, GLG, Group H, Guidepoint, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Prime Oncology, Seattle Genetics, Takeda, Trieza Therapeutics, and WebMD; and other ownership interests in Molecular Match (adviser), OncoResponse (founder), and Presagia (founder and adviser). M.A. Curran reports personal fees from ImmunoGenesis, Inc., Alligator Bioscience, Inc., ImmunOs, Inc., ImmunoMet, Inc., Oncoresponse, Inc., Pieris, Inc., Nurix, Inc., Aptevo, Inc., Merck, Inc., Oncomed, Inc., Kineta, Inc., Servier, Inc., Salarius, Inc., Xencor, Inc., and Agenus, Inc. outside the submitted work, as well as a patent for “Human PD-L1 Antibodies and Methods of Use Therefor” pending and licensed to ImmunoGenesis, Inc. and a patent for “Dual Specificity Antibodies Which Bind Both PD-L1 and PD-L2 and Prevent Their Binding to PD-1” pending and licensed to ImmunoGenesis, Inc. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
The authors thank The University of Texas MD Anderson Melanoma Moonshot Program and the Williams family for providing funding for these studies. A.R. Jaiswal was supported by a Cancer Prevention & Research Institute of Texas (CPRIT) Research Training Award (RP170067). A.J. Liu is supported by a Marilyn and Frederick R. Lummis, Jr., MD, Fellowship in Biomedical Sciences. C.R. Ager was supported by NIH TL1 fellowships (TL1TR000369 and TL1TR000371).
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - Despite the clinical success of T-cell checkpoint blockade, most patients with cancer still fail to have durable responses to immunotherapy. The molecular mechanisms driving checkpoint blockade resistance, whether preexisting or evolved, remain unclear. To address this critical knowledge gap, we treated B16 melanoma with the combination of CTLA-4, PD-1, and PD-L1 blockade and a Flt3 ligand vaccine (≥75% curative), isolated tumors resistant to therapy, and serially passaged them in vivo with the same treatment regimen until they developed complete resistance. Using gene expression analysis and immunogenomics, we determined the adaptations associated with this resistance phenotype. Checkpoint resistance coincided with acquisition of a “hypermetabolic” phenotype characterized by coordinated upregulation of the glycolytic, oxidoreductase, and mitochondrial oxidative phosphorylation pathways. These resistant tumors flourished under hypoxic conditions, whereas metabolically starved T cells lost glycolytic potential, effector function, and the ability to expand in response to immunotherapy. Furthermore, we found that checkpoint-resistant versus -sensitive tumors could be separated by noninvasive MRI imaging based solely on their metabolic state. In a cohort of patients with melanoma resistant to both CTLA-4 and PD-1 blockade, we observed upregulation of pathways indicative of a similar hypermetabolic state. Together, these data indicated that melanoma can evade T-cell checkpoint blockade immunotherapy by adapting a hypermetabolic phenotype.
AB - Despite the clinical success of T-cell checkpoint blockade, most patients with cancer still fail to have durable responses to immunotherapy. The molecular mechanisms driving checkpoint blockade resistance, whether preexisting or evolved, remain unclear. To address this critical knowledge gap, we treated B16 melanoma with the combination of CTLA-4, PD-1, and PD-L1 blockade and a Flt3 ligand vaccine (≥75% curative), isolated tumors resistant to therapy, and serially passaged them in vivo with the same treatment regimen until they developed complete resistance. Using gene expression analysis and immunogenomics, we determined the adaptations associated with this resistance phenotype. Checkpoint resistance coincided with acquisition of a “hypermetabolic” phenotype characterized by coordinated upregulation of the glycolytic, oxidoreductase, and mitochondrial oxidative phosphorylation pathways. These resistant tumors flourished under hypoxic conditions, whereas metabolically starved T cells lost glycolytic potential, effector function, and the ability to expand in response to immunotherapy. Furthermore, we found that checkpoint-resistant versus -sensitive tumors could be separated by noninvasive MRI imaging based solely on their metabolic state. In a cohort of patients with melanoma resistant to both CTLA-4 and PD-1 blockade, we observed upregulation of pathways indicative of a similar hypermetabolic state. Together, these data indicated that melanoma can evade T-cell checkpoint blockade immunotherapy by adapting a hypermetabolic phenotype.
UR - http://www.scopus.com/inward/record.url?scp=85097246974&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85097246974&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-19-0005
DO - 10.1158/2326-6066.CIR-19-0005
M3 - Article
C2 - 32917656
AN - SCOPUS:85097246974
SN - 2326-6066
VL - 8
SP - 1365
EP - 1380
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 11
ER -