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26.10.2021 | Original Article

4-(N)-Docosahexaenoyl 2’, 2’-difluorodeoxycytidine induces immunogenic cell death in colon and pancreatic carcinoma models as a single agent

verfasst von: Stephanie Hufnagel, Haiyue Xu, Michael F. Colemam, Solange A. Valdes, Kristyn A. Liu, Stephen D. Hursting, Zhengrong Cui

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 1/2022

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Abstract

Purpose

Docosahexaenoyl difluorodeoxycytidine (DHA–dFdC) is an amide with potent, broad-spectrum antitumor activity. In the present study, DHA–dFdC’s ability to induce immunogenic cell death (ICD) was tested using CT26 mouse colorectal cancer cells, an established cell line commonly used for identifying ICD inducers, as well as Panc-02 mouse pancreatic cancer cells.

Methods

The three primary surrogate markers of ICD (i.e., calreticulin (CRT) surface translocation, ATP release, and high mobility group box 1 protein (HMGB1) release) were measured in vitro. To confirm DHA–dFdC’s ability to induce ICD in vivo, the gold standard mouse vaccination studies were conducted using both CT26 and Panc-02 models. Additionally, the effect of DHA–dFdC on tumor response to anti-programmed cell death protein 1 monoclonal antibody (anti-PD-1 mAb) were tested in mice with pre-established Panc-02 tumors. RNA sequencing experiments were conducted on PANC-1 human pancreatic cancer cells treated with DHA–dFdC, dFdC, or vehicle control in vitro.

Results

DHA–dFdC elicited CRT surface translocation and ATP and HMGB1 release in both cell lines. Immunization of mice with CT26 or Panc-02 cells pretreated with DHA–dFdC prevented or delayed the development of corresponding secondary live challenge tumor. DHA–dFdC enabled Panc-02 tumors to respond to anti-PD-1 mAb. RNA sequencing experiments revealed that DHA–dFdC and dFdC differentially impacted genes related to the KRAS, TP53, and inflammatory pathways, and DHA–dFdC enriched for the unfolded protein response (UPR) compared to control, providing insight into DHA–dFdC's potential mechanism of inducing ICD.

Conclusion

DHA–dFdC is a bona fide ICD inducer and can render pancreatic tumors responsive to anti-PD-1 mAb therapy.

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Bradley MO, Webb NL, Anthony FH, Devanesan P, Witman PA, Hemamalini S et al (2001) Tumor targeting by covalent conjugation of a natural fatty acid to paclitaxel. Clin Cancer Res 7(10):3229–3238PubMed

Wang Y, Li L, Jiang W, Larrick JW (2005) Synthesis and evaluation of a DHA and 10-hydroxycamptothecin conjugate. Bioorg Med Chem 13(19):5592–5599CrossRef

Wang Y, Li L, Jiang W, Yang Z, Zhang Z (2006) Synthesis and preliminary antitumor activity evaluation of a DHA and doxorubicin conjugate. Bioorg Med Chem Lett 16(11):2974–2977. https://doi.org/10.1016/j.bmcl.2006.02.066CrossRefPubMed

Naguib YW, Lansakara-P D, Lashinger LM, Rodriguez BL, Valdes S, Niu M et al (2016) Synthesis, characterization, and in vitro and in vivo evaluations of 4-(N)-Docosahexaenoyl 2′, 2′-Difluorodeoxycytidine with potent and broad-spectrum antitumor activity. Neoplasia 18(1):33–48CrossRef

Altenburg JD, Harvey KA, McCray S, Xu Z, Siddiqui RA (2011) A novel 2,6-diisopropylphenyl-docosahexaenoamide conjugate induces apoptosis in T cell acute lymphoblastic leukemia cell lines. Biochem Biophys Res Commun 411(2):427–432. https://doi.org/10.1016/j.bbrc.2011.06.172CrossRefPubMed

Zhou J, Wang G, Chen Y, Wang H, Hua Y, Cai Z (2019) Immunogenic cell death in cancer therapy: present and emerging inducers. J Cell Mol Med 23(8):4854–4865. https://doi.org/10.1111/jcmm.14356CrossRefPubMedPubMedCentral

Rufo N, Garg AD, Agostinis P (2017) The unfolded protein response in immunogenic cell death and cancer immunotherapy. Trends Cancer 3(9):643–658. https://doi.org/10.1016/j.trecan.2017.07.002CrossRefPubMed

Gebremeskel S, Lobert L, Tanner K, Walker B, Oliphant T, Clarke LE et al (2017) Natural killer T-cell immunotherapy in combination with chemotherapy-induced immunogenic cell death targets metastatic breast cancer. Cancer Immunol Res 5(12):1086–1097. https://doi.org/10.1158/2326-6066.CIR-17-0229CrossRefPubMed

Hossain DMS, Javaid S, Cai M, Zhang C, Sawant A, Hinton M et al (2018) Dinaciclib induces immunogenic cell death and enhances anti-PD-1-mediated tumor suppression. J Clin Investig 128(2):644–654CrossRef

10.

Sakakibara K, Sato T, Kufe DW, VonHoff DD, Kawabe T (2017) CBP501 induces immunogenic tumor cell death and CD8 T cell infiltration into tumors in combination with platinum, and increases the efficacy of immune checkpoint inhibitors against tumors in mice. Oncotarget 8(45):78277CrossRef

11.

Zhao X, Yang K, Zhao R, Ji T, Wang X, Yang X et al (2016) Inducing enhanced immunogenic cell death with nanocarrier-based drug delivery systems for pancreatic cancer therapy. Biomaterials 102:187–197. https://doi.org/10.1016/j.biomaterials.2016.06.032CrossRefPubMed

12.

Kepp O, Senovilla L, Vitale I, Vacchelli E, Adjemian S, Agostinis P et al (2014) Consensus guidelines for the detection of immunogenic cell death. Oncoimmunology 3(9):e955691. https://doi.org/10.4161/21624011.2014.955691CrossRefPubMedPubMedCentral

13.

Kepp O, Senovilla L, Kroemer G (2014) Immunogenic cell death inducers as anticancer agents. Oncotarget 5(14):5190CrossRef

14.

Bezu L, Gomes-da-Silva LC, Dewitte H, Breckpot K, Fucikova J, Spisek R et al (2015) Combinatorial strategies for the induction of immunogenic cell death. Front Immunol 6:187PubMedPubMedCentral

15.

Jakobsen CH, Storvold GL, Bremseth H, Follestad T, Sand K, Mack M et al (2008) DHA induces ER stress and growth arrest in human colon cancer cells: associations with cholesterol and calcium homeostasis. J Lipid Res 49(10):2089–2100. https://doi.org/10.1194/jlr.M700389-JLR200CrossRefPubMedPubMedCentral

16.

Molinari R, D’Eliseo D, Manzi L, Zolla L, Velotti F, Merendino N (2011) The n3-polyunsaturated fatty acid docosahexaenoic acid induces immunogenic cell death in human cancer cell lines via pre-apoptotic calreticulin exposure. Cancer Immunol Immunother 60(10):1503–1507. https://doi.org/10.1007/s00262-011-1074-7CrossRefPubMed

17.

D’Eliseo D, Di Renzo L, Santoni A, Velotti F (2017) Docosahexaenoic acid (DHA) promotes immunogenic apoptosis in human multiple myeloma cells, induces autophagy and inhibits STAT3 in both tumor and dendritic cells. Genes Cancer 8(1–2):426CrossRef

18.

Zhao T, Ren H, Jia L, Chen J, Xin W, Yan F et al (2015) Inhibition of HIF-1α by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma. Oncotarget 6(4):2250. https://doi.org/10.18632/oncotarget.2948CrossRefPubMed

19.

Tesniere A, Schlemmer F, Boige V, Kepp O, Martins I, Ghiringhelli F et al (2010) Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 29(4):482–491. https://doi.org/10.1038/onc.2009.356CrossRefPubMed

20.

Duewell P, Steger A, Lohr H, Bourhis H, Hoelz H, Kirchleitner S et al (2014) RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8+ T cells. Cell Death Differ 21(12):1825. https://doi.org/10.1038/cdd.2014.96CrossRefPubMedPubMedCentral

21.

Kabacaoglu D, Ciecielski KJ, Ruess DA, Algul H (2018) Immune checkpoint inhibition for pancreatic Ductal adenocarcinoma: current limitations and future options. Front Immunol 9:1878. https://doi.org/10.3389/fimmu.2018.01878CrossRefPubMedPubMedCentral

22.

Lu J, Liu X, Liao Y-P, Salazar F, Sun B, Jiang W et al (2017) Nano-enabled pancreas cancer immunotherapy using immunogenic cell death and reversing immunosuppression. Nat Commun 8(1):1811CrossRef

23.

Liu P, Zhao L, Pol J, Levesque S, Petrazzuolo A, Pfirschke C et al (2019) Crizotinib-induced immunogenic cell death in non-small cell lung cancer. Nat Commun 10(1):1486CrossRef

24.

Wu J, Waxman DJ (2018) Immunogenic chemotherapy: dose and schedule dependence and combination with immunotherapy. Cancer Lett 419:210–221. https://doi.org/10.1016/j.canlet.2018.01.050CrossRefPubMedPubMedCentral

25.

Foley K, Kim V, Jaffee E, Zheng L (2016) Current progress in immunotherapy for pancreatic cancer. Cancer Lett 381(1):244–251. https://doi.org/10.1016/j.canlet.2015.12.020CrossRefPubMed

26.

Upadhrasta S, Zheng L (2019) Strategies in developing immunotherapy for pancreatic cancer: recognizing and correcting multiple immune “defects” in the tumor microenvironment. J Clin Med 8(9):1472. https://doi.org/10.3390/jcm8091472CrossRefPubMedCentral

27.

Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C et al (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15(23):7412–7420. https://doi.org/10.1158/1078-0432.CCR-09-1624CrossRefPubMed

28.

Zheng NN, Zhou M, Sun F, Huai MX, Zhang Y, Qu CY et al (2020) Combining protein arginine methyltransferase inhibitor and anti-programmed death-ligand-1 inhibits pancreatic cancer progression. World J Gastroenterol 26(26):3737–3749. https://doi.org/10.3748/wjg.v26.i26.3737CrossRefPubMedPubMedCentral

29.

Azad A, Yin Lim S, D’Costa Z, Jones K, Diana A, Sansom OJ et al (2017) PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy. EMBO Mol Med 9(2):167–180. https://doi.org/10.15252/emmm.201606674CrossRefPubMed

30.

Luheshi NM, Coates-Ulrichsen J, Harper J, Mullins S, Sulikowski MG, Martin P et al (2016) Transformation of the tumour microenvironment by a CD40 agonist antibody correlates with improved responses to PD-L1 blockade in a mouse orthotopic pancreatic tumour model. Oncotarget 7(14):18508–18520. https://doi.org/10.18632/oncotarget.7610CrossRefPubMedPubMedCentral

31.

Cui Z, Lansakara-p DS (2019) Nucleobase analogue derivatives and their applications. Google Patents

32.

Fryer RA, Barlett B, Galustian C, Dalgleish AG (2011) Mechanisms underlying gemcitabine resistance in pancreatic cancer and sensitisation by the iMiD lenalidomide. Anticancer Res 31(11):3747–3756PubMed

33.

Deer EL, Gonzalez-Hernandez J, Coursen JD, Shea JE, Ngatia J, Scaife CL et al (2010) Phenotype and genotype of pancreatic cancer cell lines. Pancreas 39(4):425–435. https://doi.org/10.1097/MPA.0b013e3181c15963CrossRefPubMedPubMedCentral

34.

Waters AM, Der CJ (2018) KRAS: the critical driver and therapeutic target for pancreatic cancer. Cold Spring Harb Perspect Med 8(9):a031435. https://doi.org/10.1101/cshperspect.a031435CrossRefPubMedPubMedCentral

35.

Li Z, Yu X, Werner J, Bazhin AV, D’Haese JG (2019) The role of interleukin-18 in pancreatitis and pancreatic cancer. Cytokine Growth Factor Rev 50:1–12. https://doi.org/10.1016/j.cytogfr.2019.11.001CrossRefPubMed

36.

Terme M, Ullrich E, Aymeric L, Meinhardt K, Desbois M, Delahaye N et al (2011) IL-18 induces PD-1-dependent immunosuppression in cancer. Cancer Res 71(16):5393–5399. https://doi.org/10.1158/0008-5472.CAN-11-0993CrossRefPubMed

37.

Hargadon KM (2016) Dysregulation of TGFbeta1 activity in cancer and its influence on the quality of anti-tumor immunity. J Clin Med 5(9):76. https://doi.org/10.3390/jcm5090076CrossRefPubMedCentral

38.

Bezu L, Sauvat A, Humeau J, Gomes-da-Silva LC, Iribarren K, Forveille S et al (2018) eIF2α phosphorylation is pathognomonic for immunogenic cell death. Cell Death Differ 25(8):1375–1393CrossRef

Titel: 4-(N)-Docosahexaenoyl 2’, 2’-difluorodeoxycytidine induces immunogenic cell death in colon and pancreatic carcinoma models as a single agent
verfasst von: Stephanie Hufnagel
Haiyue Xu
Michael F. Colemam
Solange A. Valdes
Kristyn A. Liu
Stephen D. Hursting
Zhengrong Cui
Publikationsdatum: 26.10.2021
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 1/2022
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-021-04367-2

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4-(N)-Docosahexaenoyl 2’, 2’-difluorodeoxycytidine induces immunogenic cell death in colon and pancreatic carcinoma models as a single agent