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Combination therapy for hepatocellular carcinoma with diacylglycerol kinase alpha inhibition and anti-programmed cell death-1 ligand blockade

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Abstract

Activation of diacylglycerol kinase alpha (DGKα) augments proliferation and suppresses apoptosis of cancer cells and induces T lymphocyte anergy. We investigated the dual effects of DGKα inhibition on tumorigenesis and anti-tumor immunity with the aim of establishing a novel therapeutic strategy for cancer. We examined the effects of a DGKα inhibitor (DGKAI) on liver cancer cell proliferation and cytokine production by immune cells in vitro and on tumorigenesis and host immunity in a hepatocellular carcinoma (HCC) mouse model. Oral DGKAI significantly suppressed tumor growth and prolonged survival in model mice. Tumor infiltration of T cells and dendritic cells was also enhanced in mice treated with DGKAI, and the production of cytokines and cytotoxic molecules by CD4+ and CD8+ T cells was increased. Depletion of CD8+ T cells reduced the effect of DGKAI. Furthermore, interferon-γ stimulation augmented the expression of programmed cell death-1 ligand (PD-L1) on cancer cells, and DGKAI plus an anti-PD-L1 antibody strongly suppressed the tumor growth. These results suggest that DGKα inhibition may be a promising new treatment strategy for HCC.

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Abbreviations

BMDC:

Bone marrow-derived dendritic cell

DGK:

Diacylglycerol kinase

DGKAI:

Diacylglycerol kinase alpha inhibitor

ERK:

Extracellular signal-regulated kinase

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

HCC:

Hepatocellular carcinoma

JNK:

C-Jun N-terminal kinase

OVA:

Ovalbumin

PBMC:

Peripheral blood mononuclear cell

PD-1:

Programmed cell death-1

PD-L1:

Programmed cell death-1 ligand

TCR:

T cell receptor

TIL:

Tumor-infiltrating lymphocyte

References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359-386. https://doi.org/10.1002/ijc.29210

    Article  CAS  PubMed  Google Scholar 

  2. Kudo M, Izumi N, Kubo S, Kokudo N, Sakamoto M, Shiina S, Tateishi R, Nakashima O, Murakami T, Matsuyama Y, Takahashi A, Miyata H, Takayama T (2020) Report of the 20th Nationwide follow-up survey of primary liver cancer in Japan. Hepatol Res 50(1):15–46. https://doi.org/10.1111/hepr.13438

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kato A, Miyazaki M, Ambiru S, Yoshitomi H, Ito H, Nakagawa K, Shimizu H, Yokosuka O, Nakajima N (2001) Multidrug resistance gene (MDR-1) expression as a useful prognostic factor in patients with human hepatocellular carcinoma after surgical resection. J Surg Oncol 78(2):110–115. https://doi.org/10.1002/jso.1129

    Article  CAS  PubMed  Google Scholar 

  4. Jiang W, Lu Z, He Y, Diasio RB (1997) Dihydropyrimidine dehydrogenase activity in hepatocellular carcinoma: implication in 5-fluorouracil-based chemotherapy. Clin Cancer Res 3(3):395–399

    CAS  PubMed  Google Scholar 

  5. Sakane F, Mizuno S, Komenoi S (2016) Diacylglycerol kinases as emerging potential drug targets for a variety of diseases: an update. Front Cell Dev Biol 4:82. https://doi.org/10.3389/fcell.2016.00082

    Article  PubMed  PubMed Central  Google Scholar 

  6. Yanagisawa K, Yasuda S, Kai M, Imai S, Yamada K, Yamashita T, Jimbow K, Kanoh H, Sakane F (2007) Diacylglycerol kinase alpha suppresses tumor necrosis factor-alpha-induced apoptosis of human melanoma cells through NF-kappaB activation. Biochim Biophys Acta 1771(4):462–474. https://doi.org/10.1016/j.bbalip.2006.12.008

    Article  CAS  PubMed  Google Scholar 

  7. Takeishi K, Taketomi A, Shirabe K, Toshima T, Motomura T, Ikegami T, Yoshizumi T, Sakane F, Maehara Y (2012) Diacylglycerol kinase alpha enhances hepatocellular carcinoma progression by activation of Ras-Raf-MEK-ERK pathway. J Hepatol 57(1):77–83. https://doi.org/10.1016/j.jhep.2012.02.026

    Article  CAS  PubMed  Google Scholar 

  8. Yamaki A, Akiyama R, Murakami C, Takao S, Murakami Y, Mizuno S, Takahashi D, Kado S, Taketomi A, Shirai Y, Goto K, Sakane F (2019) Diacylglycerol kinase α-selective inhibitors induce apoptosis and reduce viability of melanoma and several other cancer cell lines. J Cell Biochem 120(6):10043–10056. https://doi.org/10.1002/jcb.28288

    Article  CAS  PubMed  Google Scholar 

  9. Mérida I, Torres-Ayuso P, Ávila-Flores A, Arranz-Nicolás J, Andrada E, Tello-Lafoz M, Liébana R, Arcos R (2017) Diacylglycerol kinases in cancer. Adv Biol Regul 63:22–31. https://doi.org/10.1016/j.jbior.2016.09.005

    Article  CAS  PubMed  Google Scholar 

  10. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373(1):23–34. https://doi.org/10.1056/NEJMoa1504030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27(4):450–461. https://doi.org/10.1016/j.ccell.2015.03.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19(11):1423–1437. https://doi.org/10.1038/nm.3394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, Coussens LM, Gabrilovich DI, Ostrand-Rosenberg S, Hedrick CC, Vonderheide RH, Pittet MJ, Jain RK, Zou W, Howcroft TK, Woodhouse EC, Weinberg RA, Krummel MF (2018) Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 24(5):541–550. https://doi.org/10.1038/s41591-018-0014-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Jung IY, Kim YY, Yu HS, Lee M, Kim S, Lee J (2018) CRISPR/Cas9-mediated knockout of DGK improves antitumor activities of human T cells. Cancer Res 78(16):4692–4703. https://doi.org/10.1158/0008-5472.Can-18-0030

    Article  CAS  PubMed  Google Scholar 

  15. Arranz-Nicolás J, Ogando J, Soutar D, Arcos-Pérez R, Meraviglia-Crivelli D, Mañes S, Mérida I, Ávila-Flores A (2018) Diacylglycerol kinase α inactivation is an integral component of the costimulatory pathway that amplifies TCR signals. Cancer Immunol Immunother 67(6):965–980. https://doi.org/10.1007/s00262-018-2154-8

    Article  CAS  PubMed  Google Scholar 

  16. Riese MJ, Wang LC, Moon EK, Joshi RP, Ranganathan A, June CH, Koretzky GA, Albelda SM (2013) Enhanced effector responses in activated CD8+ T cells deficient in diacylglycerol kinases. Cancer Res 73(12):3566–3577. https://doi.org/10.1158/0008-5472.Can-12-3874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sakane F, Yamada K, Kanoh H, Yokoyama C, Tanabe T (1990) Porcine diacylglycerol kinase sequence has zinc finger and E-F hand motifs. Nature 344(6264):345–348. https://doi.org/10.1038/344345a0

    Article  CAS  PubMed  Google Scholar 

  18. Olenchock BA, Guo R, Carpenter JH, Jordan M, Topham MK, Koretzky GA, Zhong XP (2006) Disruption of diacylglycerol metabolism impairs the induction of T cell anergy. Nat Immunol 7(11):1174–1181. https://doi.org/10.1038/ni1400

    Article  CAS  PubMed  Google Scholar 

  19. Riese MJ, Moon EK, Johnson BD, Albelda SM (2016) Diacylglycerol kinases (DGKs): novel targets for improving T cell activity in cancer. Front Cell Dev Biol 4:108. https://doi.org/10.3389/fcell.2016.00108

    Article  PubMed  PubMed Central  Google Scholar 

  20. Guo R, Wan CK, Carpenter JH, Mousallem T, Boustany RM, Kuan CT, Burks AW, Zhong XP (2008) Synergistic control of T cell development and tumor suppression by diacylglycerol kinase alpha and zeta. Proc Natl Acad Sci USA 105(33):11909–11914. https://doi.org/10.1073/pnas.0711856105

    Article  PubMed  PubMed Central  Google Scholar 

  21. Shulga YV, Topham MK, Epand RM (2011) Regulation and functions of diacylglycerol kinases. Chem Rev 111(10):6186–6208. https://doi.org/10.1021/cr1004106

    Article  CAS  PubMed  Google Scholar 

  22. Toyoshima Y, Kitamura H, Xiang H, Ohno Y, Homma S, Kawamura H, Takahashi N, Kamiyama T, Tanino M, Taketomi A (2019) IL6 modulates the immune status of the tumor microenvironment to facilitate metastatic colonization of colorectal cancer cells. Cancer Immunol Res 7(12):1944–1957. https://doi.org/10.1158/2326-6066.cir-18-0766

    Article  CAS  PubMed  Google Scholar 

  23. Ohno Y, Kitamura H, Takahashi N, Ohtake J, Kaneumi S, Sumida K, Homma S, Kawamura H, Minagawa N, Shibasaki S, Taketomi A (2016) IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4(+) T cells. Cancer Immunol Immunother 65(2):193–204. https://doi.org/10.1007/s00262-015-1791-4

    Article  CAS  PubMed  Google Scholar 

  24. Kanada Y (2013) Investigasion of the freely available easy-to-use software ‘EZR’ for medical statictics. Bone Marrow Transplantat 48:452–458. https://doi.org/10.1038/bmt.2021.224

    Article  Google Scholar 

  25. Cheng AL, Hsu C, Chan SL, Choo SP, Kudo M (2020) Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma. J Hepatol 72(2):307–319. https://doi.org/10.1016/j.jhep.2019.09.025

    Article  CAS  PubMed  Google Scholar 

  26. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL (2020) Atezolizumab plus Bevacizumab in Unresectable hepatocellular Carcinoma. N Engl J Med 382(20):1894–1905. https://doi.org/10.1056/NEJMoa1915745

    Article  CAS  PubMed  Google Scholar 

  27. Arranz-Nicolás J, Martin-Salgado M, Adán-Barrientos I, Liébana R, Del Carmen M-O, Leitner J, Steinberger P, Ávila-Flores A, Merida I (2021) Diacylglycerol kinase α inhibition cooperates with PD-1-targeted therapies to restore the T cell activation program. Cancer Immunol Immunother. https://doi.org/10.1007/s00262-021-02924-5

    Article  PubMed  Google Scholar 

  28. Noessner E (2017) DGK-α: a checkpoint in cancer-mediated immuno-inhibition and target for immunotherapy. Front Cell Dev Biol 5:16. https://doi.org/10.3389/fcell.2017.00016

    Article  PubMed  PubMed Central  Google Scholar 

  29. Sun C, Mezzadra R, Schumacher TN (2018) Regulation and function of the PD-L1 checkpoint. Immunity 48(3):434–452. https://doi.org/10.1016/j.immuni.2018.03.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yao W, He JC, Yang Y, Wang JM, Qian YW, Yang T, Ji L (2017) The prognostic value of tumor-infiltrating lymphocytes in hepatocellular carcinoma: a systematic review and meta-analysis. Sci Rep 7(1):7525. https://doi.org/10.1038/s41598-017-08128-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liu Z, Zhao Y, Fang J, Cui R, Xiao Y, Xu Q (2017) SHP2 negatively regulates HLA-ABC and PD-L1 expression via STAT1 phosphorylation in prostate cancer cells. Oncotarget 8(32):53518–53530. https://doi.org/10.18632/oncotarget.18591

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hui E, Cheung J, Zhu J, Su X, Taylor MJ, Wallweber HA, Sasmal DK, Huang J, Kim JM, Mellman I, Vale RD (2017) T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science (New York, NY) 355(6332):1428–1433. https://doi.org/10.1126/science.aaf1292

    Article  CAS  Google Scholar 

  33. Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, Saito T (2012) Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med 209(6):1201–1217. https://doi.org/10.1084/jem.20112741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cao X, Cai SF, Fehniger TA, Song J, Collins LI, Piwnica-Worms DR, Ley TJ (2007) Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 27(4):635–646. https://doi.org/10.1016/j.immuni.2007.08.014

    Article  CAS  PubMed  Google Scholar 

  35. Merida I, Graziani A, Sakane F (2017) Editorial: diacylglycerol kinase signalling. Front Cell Dev Biol 5:84. https://doi.org/10.3389/fcell.2017.00084

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ohno Y, Toyoshima Y, Yurino H, Monma N, Xiang H, Sumida K, Kaneumi S, Terada S, Hashimoto S, Ikeo K, Homma S, Kawamura H, Takahashi N, Taketomi A, Kitamura H (2017) Lack of interleukin-6 in the tumor microenvironment augments type-1 immunity and increases the efficacy of cancer immunotherapy. Cancer Sci 108(10):1959–1966. https://doi.org/10.1111/cas.13330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mandai M, Hamanishi J, Abiko K, Matsumura N, Baba T, Konishi I (2016) Dual faces of IFNγ in cancer progression: a role of PD-L1 induction in the determination of pro- and antitumor immunity. Clin Cancer Res 22(10):2329–2334. https://doi.org/10.1158/1078-0432.ccr-16-0224

    Article  CAS  PubMed  Google Scholar 

  38. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528):568–571. https://doi.org/10.1038/nature13954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Eroglu Z, Zaretsky JM, Hu-Lieskovan S, Kim DW, Algazi A, Johnson DB, Liniker E, Ben K, Munhoz R, Rapisuwon S, Gherardini PF, Chmielowski B, Wang X, Shintaku IP, Wei C, Sosman JA, Joseph RW, Postow MA, Carlino MS, Hwu WJ, Scolyer RA, Messina J, Cochran AJ, Long GV, Ribas A (2018) High response rate to PD-1 blockade in desmoplastic melanomas. Nature 553(7688):347–350. https://doi.org/10.1038/nature25187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kim JM, Chen DS (2016) Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol 27(8):1492–1504. https://doi.org/10.1093/annonc/mdw217

    Article  CAS  PubMed  Google Scholar 

  41. Abiko K, Matsumura N, Hamanishi J, Horikawa N, Murakami R, Yamaguchi K, Yoshioka Y, Baba T, Konishi I, Mandai M (2015) IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. Br J Cancer 112(9):1501–1509. https://doi.org/10.1038/bjc.2015.101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sharma P, Allison JP (2015) The future of immune checkpoint therapy. Science (New York, NY) 348(6230):56–61. https://doi.org/10.1126/science.aaa8172

    Article  CAS  Google Scholar 

  43. Calderaro J, Rousseau B, Amaddeo G, Mercey M, Charpy C, Costentin C, Luciani A, Zafrani ES, Laurent A, Azoulay D, Lafdil F, Pawlotsky JM (2016) Programmed death ligand 1 expression in hepatocellular carcinoma: relationship with clinical and pathological features. Hepatology (Baltimore, MD) 64(6):2038–2046. https://doi.org/10.1002/hep.28710

    Article  CAS  Google Scholar 

  44. Dai X, Xue J, Hu J, Yang SL, Chen GG, Lai PBS, Yu C, Zeng C, Fang X, Pan X, Zhang T (2017) Positive expression of programmed death ligand 1 in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. Transl Oncol 10(4):511–517. https://doi.org/10.1016/j.tranon.2017.03.009

    Article  PubMed  PubMed Central  Google Scholar 

  45. Zou W, Wolchok JD, Chen L (2016) PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med 8(328):328rv324. https://doi.org/10.1126/scitranslmed.aad7118

  46. Liao H, Chen W, Dai Y, Richardson JJ, Guo J, Yuan K, Zeng Y, Xie K (2019) Expression of programmed cell death-ligands in hepatocellular carcinoma: correlation with immune microenvironment and survival outcomes. Front Oncol 9:883. https://doi.org/10.3389/fonc.2019.00883

    Article  PubMed  PubMed Central  Google Scholar 

  47. Wu K, Kryczek I, Chen L, Zou W, Welling TH (2009) Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7–H1/programmed death-1 interactions. Cancer Res 69(20):8067–8075. https://doi.org/10.1158/0008-5472.can-09-0901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Fu L, Li S, Xiao W, Yu K, Li S, Yuan S, Shen J, Dong X, Fang Z, Zhang J, Chen S, Li W, You H, Xia X, Kang T, Tan J, Chen G, Yang AK, Gao Y, Zhou P (2021) DGKA mediates resistance to PD-1 blockade. Cancer Immunol Res 9(4):371–385. https://doi.org/10.1158/2326-6066.CIR-20-0216

    Article  CAS  PubMed  Google Scholar 

  49. Olmez I, Love S, Xiao A, Manigat L, Randolph P, McKenna BD, Neal BP, Boroda S, Li M, Brenneman B, Abounader R, Floyd D, Lee J, Nakano I, Godlewski J, Bronisz A, Sulman EP, Mayo M, Gioeli D, Weber M, Harris TE, Purow B (2018) Targeting the mesenchymal subtype in glioblastoma and other cancers via inhibition of diacylglycerol kinase alpha. Neuro Oncol 20(2):192–202. https://doi.org/10.1093/neuonc/nox119

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. T. Kamiyama and members of the Department of Gastroenterological Surgery I, Hokkaido University, for providing clinical samples, Dr. Y. Hatanaka, Dr. K. Hatanaka, Dr. S. Kii, N. Kobayashi, and H. Xiang for technical assistance and thoughtful advice. The authors thank Ono Pharmaceutical Co., Ltd. for the donation of DGKAI and secretarial assistance. The authors thank Susan Furness, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Funding

This work was partially supported by a Grant-in-Aid for Scientific Research B (19H03724 to AT) and for Challenging Research (Exploratory) (18K19571 to AT) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (MEXT), by Ono Pharmaceutical Co. Ltd., by Akiyama Life Science Foundation, and by the Joint Research Program of the Institute for Genetic Medicine, Hokkaido University. All funding sources had no involvement in study design and in the decision to submit the article for publication.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, N15 W7 Kita-ku, Sapporo, Hokkaido, 060-8638, Japan

    Naoki Okada, Ko Sugiyama, Shunsuke Shichi & Akinobu Taketomi

  2. Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Faculty of Agriculture, Kobe University, Kobe, Japan

    Yasuhito Shirai

  3. Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata, Japan

    Kaoru Goto

  4. Department of Chemistry, Graduate School of Science, Chiba University, Chiba, Japan

    Fumio Sakane

  5. Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan

    Hidemitsu Kitamura

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  1. Naoki Okada
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Contributions

NO, YS, KG, FS, HK, AT designed the study. NO, KS, SS, HK collected the data. NO, KS, SS, HK, AT analyzed the data. All authors interpreted the data and prepared and reviewed the manuscript.

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Correspondence to Akinobu Taketomi.

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Written informed consent was obtained from all participants.

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All mouse experiments were approved by the Animal Ethics Committee of Hokkaido University and conducted in accordance with the institution’s Guide for the Care and Use of Laboratory Animals. The experiments conformed to the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines.

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The human study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Institutional Review Boards of Hokkaido University, Hokkaido University Graduate School of Medicine, and the Institute for Genetic Medicine.

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Okada, N., Sugiyama, K., Shichi, S. et al. Combination therapy for hepatocellular carcinoma with diacylglycerol kinase alpha inhibition and anti-programmed cell death-1 ligand blockade. Cancer Immunol Immunother 71, 889–903 (2022). https://doi.org/10.1007/s00262-021-03041-z

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