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image of Carbonic Anhydrase IX and Cyclooxygenase-2 Regulation in Renal Cell Carcinoma and Impact on Therapeutic Efficiency of Anti-CAIX CAR T cells

Abstract

Background

Clear cell renal cell carcinoma (ccRCC) is the most prevalent of renal cancers, with a 5-year survival rate of less than 10% for metastatic cases. The most efficient current strategies to treat ccRCC in advanced settings slightly increase progression-free survival. Chimeric antigen receptor T cells (CAR T cells) targeting carbonic anhydrase IX (CAIX) have reemerged as a promising alternative to ccRCC treatment based on recent preclinical data. CAIX and cyclooxygenase-2 (COX-2) are key players in tumor progression across various malignancies, overexpressed in 95% and 50% of ccRCC cases, respectively.

Methods

This study employed analysis to examine the expression of CAIX and COX-2 in ccRCC cell lines. The effects of celecoxib, anti-CAIX monoclonal antibodies, and anti-CAIX CAR T cells were evaluated using immunofluorescence microscopy and flow cytometry techniques.

Results

Herein, we show a positive correlation between CAIX and COX-2 expression in ccRCC cell lines and in silico. Notably, COX-2 blockade with celecoxib led to a significant downregulation of CAIX expression in ccRCC cell lines. This effect is retroactive since treatment of these ccRCC cells with two different anti-CAIX monoclonal antibodies (mAbs) resulted in the downregulation of COX-2 expression. The association of celecoxib with anti-CAIX CAR T cell therapy impaired their cytotoxic potential over ccRCC , depending on CAIX cellular density.

Conclusion

These findings suggest a regulatory interaction between CAIX and COX-2 levels, indicating that COX-2 inhibitors may diminish the efficacy of CAIX-targeted therapies and should be avoided in combination treatments.

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2025-06-27
2025-09-13

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References

  1. Jonasch E. Walker C.L. Rathmell W.K. Clear cell renal cell carcinoma ontogeny and mechanisms of lethality. Nat. Rev. Nephrol. 2021 17 4 245 261 10.1038/s41581‑020‑00359‑2 33144689
    [Google Scholar]
  2. Escudier B. Porta C. Schmidinger M. Algaba F. Patard J.J. Khoo V. Eisen T. Horwich A. Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014 25 iii49 iii56 (Suppl. 3) 10.1093/annonc/mdu259 25210086
    [Google Scholar]
  3. Berglund A. Amankwah E.K. Kim Y.C. Spiess P.E. Sexton W.J. Manley B. Park H.Y. Wang L. Chahoud J. Chakrabarti R. Yeo C.D. Luu H.N. Pietro G.D. Parker A. Park J.Y. Influence of gene expression on survival of clear cell renal cell carcinoma. Cancer Med. 2020 9 22 8662 8675 10.1002/cam4.3475 32986937
    [Google Scholar]
  4. Hu J. Tan P. Ishihara M. Bayley N.A. Schokrpur S. Reynoso J.G. Zhang Y. Lim R.J. Dumitras C. Yang L. Dubinett S.M. Jat P.S. Snick V.J. Huang J. Chin A.I. Prins R.M. Graeber T.G. Xu H. Wu L. Tumor heterogeneity in VHL drives metastasis in clear cell renal cell carcinoma. Signal Transduct. Target. Ther. 2023 8 1 155 10.1038/s41392‑023‑01362‑2 37069149
    [Google Scholar]
  5. Greco F. D’Andrea V. Zobel R.B. Mallio C.A. Radiogenomics and Texture Analysis to Detect von Hippel–Lindau (VHL) Mutation in Clear Cell Renal Cell Carcinoma. Curr. Issues Mol. Biol. 2024 46 4 3236 3250 10.3390/cimb46040203 38666933
    [Google Scholar]
  6. Yang J. Luo L. Zhao C. Li X. Wang Z. Zeng Z. Yang X. Zheng X. Jie H. Kang L. Li S. Liu S. Zhou C. Liu H. A positive feedback loop between inactive VHL-triggered histone lactylation and pdgfrβ signaling drives clear cell renal cell carcinoma progression. Int. J. Biol. Sci. 2022 18 8 3470 3483 10.7150/ijbs.73398 35637958
    [Google Scholar]
  7. Courcier J. Taille L.D.A. Nourieh M. Leguerney I. Lassau N. Ingels A. Carbonic anhydrase ix in renal cell carcinoma, implications for disease management. Int. J. Mol. Sci. 2020 21 19 7146 10.3390/ijms21197146 32998233
    [Google Scholar]
  8. Deng J. Tu S. Li L. Li G. Zhang Y. Diagnostic, predictive and prognostic molecular biomarkers in clear cell renal cell carcinoma: A retrospective study. Cancer Rep. 2024 7 6 e2116 10.1002/cnr2.2116 38837683
    [Google Scholar]
  9. Stillebroer A.B. Mulders P.F.A. Boerman O.C. Oyen W.J.G. Oosterwijk E. Carbonic anhydrase IX in renal cell carcinoma: Implications for prognosis, diagnosis, and therapy. Eur. Urol. 2010 58 1 75 83 10.1016/j.eururo.2010.03.015 20359812
    [Google Scholar]
  10. Ramachandran K. R M.B Jojo A Pooleri G.K Thomas A. Role of CAIX expression in conventional renal cell carcinomas as a diagnostic marker and its prognostic importance. Indian J. Surg. Oncol., 2021 12 1 79 84 (Suppl. 1) 10.1007/s13193‑020‑01076‑9 33994732
    [Google Scholar]
  11. Parks S.K. Chiche J. Pouyssegur J. pH control mechanisms of tumor survival and growth. J. Cell. Physiol. 2011 226 2 299 308 10.1002/jcp.22400 20857482
    [Google Scholar]
  12. Mahon B. Pinard M. McKenna R. Targeting carbonic anhydrase IX activity and expression. Molecules 2015 20 2 2323 2348 10.3390/molecules20022323 25647573
    [Google Scholar]
  13. Svastova E. Witarski W. Csaderova L. Kosik I. Skvarkova L. Hulikova A. Zatovicova M. Barathova M. Kopacek J. Pastorek J. Pastorekova S. Carbonic anhydrase IX interacts with bicarbonate transporters in lamellipodia and increases cell migration via its catalytic domain. J. Biol. Chem. 2012 287 5 3392 3402 10.1074/jbc.M111.286062 22170054
    [Google Scholar]
  14. Campos N.S.P. Souza B.S. Silva G.C.P. Porto V.A. Chalbatani G.M. Lagreca G. Janji B. Suarez E.R. Carbonic anhydrase IX: A renewed target for cancer immunotherapy. Cancers 2022 14 6 1392 10.3390/cancers14061392 35326544
    [Google Scholar]
  15. Hassanian H. Asadzadeh Z. Baghbanzadeh A. Derakhshani A. Dufour A. Khosroshahi R.N. Najafi S. Brunetti O. Silvestris N. Baradaran B. The expression pattern of Immune checkpoints after chemo/radiotherapy in the tumor microenvironment. Front. Immunol. 2022 13 938063 10.3389/fimmu.2022.938063 35967381
    [Google Scholar]
  16. Hsieh J.J. Purdue M.P. Signoretti S. Swanton C. Albiges L. Schmidinger M. Heng D.Y. Larkin J. Ficarra V. Renal cell carcinoma. Nat. Rev. Dis. Primers 2017 3 1 17009 10.1038/nrdp.2017.9 28276433
    [Google Scholar]
  17. Motzer R. Alekseev B. Rha S.Y. Porta C. Eto M. Powles T. Grünwald V. Hutson T.E. Kopyltsov E. Méndez-Vidal M.J. Kozlov V. Alyasova A. Hong S.H. Kapoor A. Gordoa A.T. Merchan J.R. Winquist E. Maroto P. Goh J.C. Kim M. Gurney H. Patel V. Peer A. Procopio G. Takagi T. Melichar B. Rolland F. Giorgi D.U. Wong S. Bedke J. Schmidinger M. Dutcus C.E. Smith A.D. Dutta L. Mody K. Perini R.F. Xing D. Choueiri T.K. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N. Engl. J. Med. 2021 384 14 1289 1300 10.1056/NEJMoa2035716 33616314
    [Google Scholar]
  18. Meng L. Collier K.A. Wang P. Li Z. Monk P. Mortazavi A. Hu Z. Spakowicz D. Zheng L. Yang Y. Emerging immunotherapy approaches for advanced clear cell renal cell carcinoma. Cells 2023 13 1 34 10.3390/cells13010034 38201238
    [Google Scholar]
  19. Wang Y. Suarez E.R. Kastrunes G. Campos D.N.S.P. Abbas R. Pivetta R.S. Murugan N. Chalbatani G.M. D’Andrea V. Marasco W.A. Evolution of cell therapy for renal cell carcinoma. Mol. Cancer 2024 23 1 8 10.1186/s12943‑023‑01911‑x 38195534
    [Google Scholar]
  20. Chang D.K. Moniz R.J. Xu Z. Sun J. Signoretti S. Zhu Q. Marasco W.A. Human anti-CAIX antibodies mediate immune cell inhibition of renal cell carcinoma in vitro and in a humanized mouse model in vivo. Mol. Cancer 2015 14 1 119 10.1186/s12943‑015‑0384‑3 26062742
    [Google Scholar]
  21. Benmebarek M.R. Karches C.H. Cadilha B.L. Lesch S. Endres S. Kobold S. Killing Mechanisms of Chimeric Antigen Receptor (CAR) T Cells. Int. J. Mol. Sci. 2019 20 6 1283 10.3390/ijms20061283 30875739
    [Google Scholar]
  22. Bauer S. Oosterwijk-Wakka J.C. Adrian N. Oosterwijk E. Fischer E. Wüest T. Stenner F. Perani A. Cohen L. Knuth A. Divgi C. Jäger D. Scott A.M. Ritter G. Old L.J. Renner C. Targeted therapy of renal cell carcinoma: Synergistic activity of cG250‐TNF and IFNg. Int. J. Cancer 2009 125 1 115 123 10.1002/ijc.24359 19384924
    [Google Scholar]
  23. Wang Y. Buck A. Piel B. Zerefa L. Murugan N. Coherd C.D. Miklosi A.G. Johal H. Bastos R.N. Huang K. Ficial M. Laimon Y.N. Signoretti S. Zhong Z. Hoang S.M. Kastrunes G.M. Grimaud M. Fayed A. Yuan H.C. Nguyen Q.D. Thai T. Ivanova E.V. Paweletz C.P. Wu M.R. Choueiri T.K. Wee J.O. Freeman G.J. Barbie D.A. Marasco W.A. Affinity fine-tuning anti-CAIX CAR-T cells mitigate on-target off-tumor side effects. Mol. Cancer 2024 23 1 56 10.1186/s12943‑024‑01952‑w 38491381
    [Google Scholar]
  24. Badawi W.A. Rashed M. Nocentini A. Bonardi A. Abd-Alhaseeb M.M. Al-Rashood S.T. Veerakanellore G.B. Majrashi T.A. Elkaeed E.B. Elgendy B. Gratteri P. Supuran C.T. Eldehna W.M. Elagawany M. Identification of new 4-(6-oxopyridazin-1-yl)benzenesulfonamides as multi-target anti-inflammatory agents targeting carbonic anhydrase, COX-2 and 5-LOX enzymes: Synthesis, biological evaluations and modelling insights. J. Enzyme Inhib. Med. Chem. 2023 38 1 2201407 10.1080/14756366.2023.2201407 37078173
    [Google Scholar]
  25. Kulesza A. Paczek L. Burdzinska A. The role of COX-2 and PGE2 in the regulation of immunomodulation and other functions of mesenchymal stromal cells. Biomedicines 2023 11 2 445 10.3390/biomedicines11020445 36830980
    [Google Scholar]
  26. Finetti F. Travelli C. Ercoli J. Colombo G. Buoso E. Trabalzini L. Prostaglandin E2 and cancer: Insight into tumor progression and immunity. Biology 2020 9 12 434 10.3390/biology9120434 33271839
    [Google Scholar]
  27. Willoughby D.A. Moore A.R. Colville-Nash P.R. COX-1, COX-2, and COX-3 and the future treatment of chronic inflammatory disease. Lancet 2000 355 9204 646 648 10.1016/S0140‑6736(99)12031‑2 10696997
    [Google Scholar]
  28. Regulski M. Regulska K. Prukała W. Piotrowska H. Stanisz B. Murias M. COX-2 inhibitors: A novel strategy in the management of breast cancer. Drug Discov. Today 2016 21 4 598 615 10.1016/j.drudis.2015.12.003 26723915
    [Google Scholar]
  29. Prima V. Kaliberova L.N. Kaliberov S. Curiel D.T. Kusmartsev S. COX2/mPGES1/PGE 2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells. Proc. Natl. Acad. Sci. USA 2017 114 5 1117 1122 10.1073/pnas.1612920114 28096371
    [Google Scholar]
  30. Jin K. Qian C. Lin J. Liu B. Cyclooxygenase-2-Prostaglandin E2 pathway: A key player in tumor-associated immune cells. Front. Oncol. 2023 13 1099811 10.3389/fonc.2023.1099811 36776289
    [Google Scholar]
  31. Chen Q. Shinohara N. Abe T. Harabayashi T. Nonomura K. Impact of cyclooxygenase-2 gene expression on tumor invasiveness in a human renal cell carcinoma cell line. J. Urol. 2004 172 6 Part 1 2153 2157 10.1097/01.ju.0000143440.08760.3a 15538221
    [Google Scholar]
  32. Li J. Hao Q. Cao W. Vadgama J.V. Wu Y. Celecoxib in breast cancer prevention and therapy. Cancer Manag. Res. 2018 10 4653 4667 10.2147/CMAR.S178567 30464589
    [Google Scholar]
  33. Dai H. Wang G. Cao W. Qi W. Chen W. Guo H. Stress granules affect the sensitivity of renal cancer cells to sorafenib by sequestering and stabilizing COX 2 mRNA. Oncol. Lett. 2023 25 6 274 10.3892/ol.2023.13860 37216166
    [Google Scholar]
  34. Tupá V. Drahošová S. Grendár M. Adamkov M. Expression and association of carbonic anhydrase IX and cyclooxygenase-2 in colorectal cancer. Pathol. Res. Pract. 2019 215 4 705 711 10.1016/j.prp.2019.01.012 30638861
    [Google Scholar]
  35. Ebert T. Bander N.H. Finstad C.L. Ramsawak R.D. Old L.J. Establishment and characterization of human renal cancer and normal kidney cell lines. Cancer Res. 1990 50 17 5531 5536 [PMID: 2386958
    [Google Scholar]
  36. Chakravarty D. Gao J. Phillips S. Kundra R. Zhang H. Wang J. Rudolph J.E. Yaeger R. Soumerai T. Nissan M.H. Chang M.T. Chandarlapaty S. Traina T.A. Paik P.K. Ho A.L. Hantash F.M. Grupe A. Baxi S.S. Callahan M.K. Snyder A. Chi P. Danila D.C. Gounder M. Harding J.J. Hellmann M.D. Iyer G. Janjigian Y.Y. Kaley T. Levine D.A. Lowery M. Omuro A. Postow M.A. Rathkopf D. Shoushtari A.N. Shukla N. Voss M.H. Paraiso E. Zehir A. Berger M.F. Taylor B.S. Saltz L.B. Riely G.J. Ladanyi M. Hyman D.M. Baselga J. Sabbatini P. Solit D.B. Schultz N. Onco K.B. A precision oncology knowledge base. JCO Precis. Oncol. 2017 2017 1 1 16 10.1200/PO.17.00011 28890946
    [Google Scholar]
  37. Suehnholz S.P. Nissan M.H. Zhang H. Kundra R. Nandakumar S. Lu C. Carrero S. Dhaneshwar A. Fernandez N. Xu B.W. Arcila M.E. Zehir A. Syed A. Brannon A.R. Rudolph J.E. Paraiso E. Sabbatini P.J. Levine R.L. Dogan A. Gao J. Ladanyi M. Drilon A. Berger M.F. Solit D.B. Schultz N. Chakravarty D. Quantifying the Expanding Landscape of Clinical Actionability for Patients with Cancer. Cancer Discov. 2024 14 1 49 65 10.1158/2159‑8290.CD‑23‑0467 37849038
    [Google Scholar]
  38. Schneider C.A. Rasband W.S. Eliceiri K.W. NIH Image to ImageJ: 25 years of image analysis. Nat. Methods 2012 9 7 671 675 10.1038/nmeth.2089 22930834
    [Google Scholar]
  39. Hsu C.Y.M. Uludağ H. A simple and rapid nonviral approach to efficiently transfect primary tissue–derived cells using polyethylenimine. Nat. Protoc. 2012 7 5 935 945 10.1038/nprot.2012.038 22517260
    [Google Scholar]
  40. Kutner R.H. Zhang X.Y. Reiser J. Production, concentration and titration of pseudotyped HIV-1-based lentiviral vectors. Nat. Protoc. 2009 4 4 495 505 10.1038/nprot.2009.22 19300443
    [Google Scholar]
  41. Charan J. Kantharia N.D. How to calculate sample size in animal studies? J. Pharmacol. Pharmacother. 2013 4 4 303 306 10.4103/0976‑500X.119726 24250214
    [Google Scholar]
  42. Suarez E.R. Chang D.K. Sun J. Sui J. Freeman G.J. Signoretti S. Zhu Q. Marasco W.A. Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model. Oncotarget 2016 7 23 34341 34355 10.18632/oncotarget.9114 27145284
    [Google Scholar]
  43. Chapman E.J. Edwards Z. Boland J.W. Maddocks M. Fettes L. Malia C. Mulvey M.R. Bennett M.I. Practice review: Evidence-based and effective management of pain in patients with advanced cancer. Palliat. Med. 2020 34 4 444 453 10.1177/0269216319896955 31980005
    [Google Scholar]
  44. Xu C. Lo A. Yammanuru A. Tallarico A.S.C. Brady K. Murakami A. Barteneva N. Zhu Q. Marasco W.A. Unique biological properties of catalytic domain directed human anti-CAIX antibodies discovered through phage-display technology. PLoS One 2010 5 3 e9625 10.1371/journal.pone.0009625 20224781
    [Google Scholar]
  45. Masferrer J.L. Leahy K.M. Koki A.T. Zweifel B.S. Settle S.L. Woerner B.M. Edwards D.A. Flickinger A.G. Moore R.J. Seibert K. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res. 2000 60 5 1306 1311 [PMID: 10728691
    [Google Scholar]
  46. Karim A. Fowler M. Jones L. Patwardhan R. Vannemreddy P. Mccarthy K. Nanda A. Cyclooxygenase-2 expression in brain metastases. Anticancer Res. 2005 25 4 2969 2971 [PMID: 16080553
    [Google Scholar]
  47. Hara S. Kondo Y. Matsuzawa I. Hashimoto Y. Kimura G. Akimoto M. Expression of cycloxygenase-2 in human bladder and renal cell carcinoma. In:Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury, 5. Honn K.V. Marnett L.J. Nigam S. Dennis E. Serhan C. Boston, MA Springer US 2002 123 126 10.1007/978‑1‑4615‑0193‑0_20
    [Google Scholar]
  48. Witton C.J. Hawe S.J.K. Cooke T.G. Bartlett J.M.S. Cyclooxygenase 2 (COX2) expression is associated with poor outcome in ER‐negative, but not ER‐positive, breast cancer. Histopathology 2004 45 1 47 54 10.1111/j.1365‑2559.2004.01898.x 15228443
    [Google Scholar]
  49. Herceg M.E. Tsiatis A.C. Halpern J.L. Holt G.E. Schwartz H.S. Keedy V.L. Cates J.M. Cyclooxygenase 2 expression in soft tissue leiomyosarcoma. Anticancer Res. 2009 29 8 2913 2917 [PMID: 19661295
    [Google Scholar]
  50. Kim H. Song J.Y. Cho J.Y. Yoon Y.S. Han H.S. Lee H.S. Ryu H.S. Choe G. Strong cytoplasmic expression of COX2 at the invasive fronts of gallbladder cancer is associated with a poor prognosis. J. Clin. Pathol. 2010 63 12 1048 1053 10.1136/jcp.2010.080713 20924037
    [Google Scholar]
  51. Kim S.K. Lim S.Y. Wang K.C. Kim Y.Y. Chi J. Choi Y. Shin H. Cho B.K. Overexpression of cyclooxygenase-2 in childhood ependymomas: Role of COX-2 inhibitor in growth and multi-drug resistance in vitro. Oncol. Rep. 2004 12 2 403 409 10.3892/or.12.2.403 15254709
    [Google Scholar]
  52. Yoshimura R. Matsuyama M. Kawahito Y. Takemoto Y. Tsuchida K. Kuratsukuri K. Segawa Y. Shinnka T. Sano H. Nakatani T. The effects of cyclooxygenase-2 inhibitors on urological cancer cells. Int. J. Mol. Med. 2004 13 6 789 793 10.3892/ijmm.13.6.789 15138613
    [Google Scholar]
  53. Suryanti S. Agustina H. Aziz A. Yulianti H. Suryawathy B. Putri L. High immunoexpression of cox-2 as a metastatic risk factor in ccrcc without PD-L1 involvement. Res. Rep. Urol. 2021 13 623 630 10.2147/RRU.S324510
    [Google Scholar]
  54. Kısmet K. Akay M.T. Abbasoǧlu O. Ercan A. Celecoxib: A potent cyclooxygenase-2 inhibitor in cancer prevention. Cancer Detect. Prev. 2004 28 2 127 142 10.1016/j.cdp.2003.12.005 15068837
    [Google Scholar]
  55. Yan M. Myung S.J. Fink S.P. Lawrence E. Lutterbaugh J. Yang P. Zhou X. Liu D. Rerko R.M. Willis J. Dawson D. Tai H.H. Barnholtz-Sloan J.S. Newman R.A. Bertagnolli M.M. Markowitz S.D. 15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors. Proc. Natl. Acad. Sci. USA 2009 106 23 9409 9413 10.1073/pnas.0902367106 19470469
    [Google Scholar]
  56. Weber A. Casini A. Heine A. Kuhn D. Supuran C.T. Scozzafava A. Klebe G. Unexpected nanomolar inhibition of carbonic anhydrase by COX-2-selective celecoxib: New pharmacological opportunities due to related binding site recognition. J. Med. Chem. 2004 47 3 550 557 10.1021/jm030912m 14736236
    [Google Scholar]
  57. Kim H.T. Cha H. Hwang K.Y. Structural insight into the inhibition of carbonic anhydrase by the COX-2-selective inhibitor polmacoxib (CG100649). Biochem. Biophys. Res. Commun. 2016 478 1 1 6 10.1016/j.bbrc.2016.07.114 27475498
    [Google Scholar]
  58. Hilvo M. Baranauskiene L. Salzano A.M. Scaloni A. Matulis D. Innocenti A. Scozzafava A. Monti S.M. Fiore D.A. Simone D.G. Lindfors M. Jänis J. Valjakka J. Pastoreková S. Pastorek J. Kulomaa M.S. Nordlund H.R. Supuran C.T. Parkkila S. Biochemical characterization of CA IX, one of the most active carbonic anhydrase isozymes. J. Biol. Chem. 2008 283 41 27799 27809 10.1074/jbc.M800938200 18703501
    [Google Scholar]
  59. Pirkebner D. Fuetsch M. Wittmann W. Weiss H. Haller T. Schramek H. Margreiter R. Amberger A. Reduction of intracellular pH inhibits constitutive expression of Cyclooxygenase‐2 in human colon cancer cells. J. Cell. Physiol. 2004 198 2 295 301 10.1002/jcp.10408 14603531
    [Google Scholar]
  60. Shafee N. Kaluz S. Ru N. Stanbridge E.J. PI3K/Akt activity has variable cell-specific effects on expression of HIF target genes, CA9 and VEGF, in human cancer cell lines. Cancer Lett. 2009 282 1 109 115 10.1016/j.canlet.2009.03.004 19342157
    [Google Scholar]
  61. Liu J. Hu X. Feng L. Lin Y. Liang S. Zhu Z. Shi S. Dong C. Carbonic anhydrase IX-targeted H-APBC nanosystem combined with phototherapy facilitates the efficacy of PI3K/mTOR inhibitor and resists HIF-1α-dependent tumor hypoxia adaptation. J. Nanobiotechnology 2022 20 1 187 10.1186/s12951‑022‑01394‑w 35413842
    [Google Scholar]
  62. Benej M. Pastorekova S. Pastorek J. Carbonic anhydrase IX: Regulation and role in cancer. Subcell. Biochem. 2014 75 199 219 10.1007/978‑94‑007‑7359‑2_11
    [Google Scholar]
  63. Gao J. Tian J. Lv Y. Shi F. Kong F. Shi H. Zhao L. Leptin induces functional activation of cyclooxygenase‐2 through JAK2/STAT3, MAPK/ERK, and PI3K/AKT pathways in human endometrial cancer cells. Cancer Sci. 2009 100 3 389 395 10.1111/j.1349‑7006.2008.01053.x 19154413
    [Google Scholar]
  64. Uddin S. Ahmed M. Hussain A. Assad L. Al-Dayel F. Bavi P. Al-Kuraya K.S. Munkarah A. Cyclooxygenase‐2 inhibition inhibits PI3K/AKT kinase activity in epithelial ovarian cancer. Int. J. Cancer 2010 126 2 382 394 10.1002/ijc.24757 19621391
    [Google Scholar]
  65. Glaviano A. Foo A.S.C. Lam H.Y. Yap K.C.H. Jacot W. Jones R.H. Eng H. Nair M.G. Makvandi P. Geoerger B. Kulke M.H. Baird R.D. Prabhu J.S. Carbone D. Pecoraro C. Teh D.B.L. Sethi G. Cavalieri V. Lin K.H. Javidi-Sharifi N.R. Toska E. Davids M.S. Brown J.R. Diana P. Stebbing J. Fruman D.A. Kumar A.P. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol. Cancer 2023 22 1 138 10.1186/s12943‑023‑01827‑6 37596643
    [Google Scholar]
  66. Janku F. Yap T.A. Meric-Bernstam F. Targeting the PI3K pathway in cancer: Are we making headway? Nat. Rev. Clin. Oncol. 2018 15 5 273 291 10.1038/nrclinonc.2018.28 29508857
    [Google Scholar]
  67. Ward C. Meehan J. Gray M. Kunkler I. Langdon S. Argyle D. Carbonic anhydrase IX (CAIX), cancer, and radiation responsiveness. Metabolites 2018 8 1 13 10.3390/metabo8010013 29439394
    [Google Scholar]
  68. Dorai T. Sawczuk I. Pastorek J. Wiernik P.H. Dutcher J.P. Role of carbonic anhydrases in the progression of renal cell carcinoma subtypes: Proposal of a unified hypothesis. Cancer Invest. 2006 24 8 754 779 10.1080/07357900601062321 17162558
    [Google Scholar]
  69. Wu L. Wei Q. Brzostek J. Gascoigne N.R.J. Signaling from T cell receptors (TCRs) and chimeric antigen receptors (CARs) on T cells. Cell. Mol. Immunol. 2020 17 6 600 612 10.1038/s41423‑020‑0470‑3 32451454
    [Google Scholar]
  70. Ferrandina G. Ranelletti F.O. Legge F. Salutari V. Martinelli E. Fattorossi A. Lorusso D. Zannoni G. Vellone V. Paglia A. Scambia G. Celecoxib up-regulates the expression of the ζ chain of T cell receptor complex in tumor-infiltrating lymphocytes in human cervical cancer. Clin. Cancer Res. 2006 12 7 2055 2060 10.1158/1078‑0432.CCR‑05‑2530 16609015
    [Google Scholar]
  71. Yang Y. Kohler M.E. Chien C.D. Sauter C.T. Jacoby E. Yan C. Hu Y. Wanhainen K. Qin H. Fry T.J. TCR engagement negatively affects CD8 but not CD4 CAR T cell expansion and leukemic clearance. Sci. Transl. Med. 2017 9 417 eaag1209 10.1126/scitranslmed.aag1209 29167392
    [Google Scholar]
  72. Yang M. Wang L. Ni M. Neuber B. Wang S. Gong W. Sauer T. Schubert M.L. Hückelhoven-Krauss A. Xia R. Ge J. Kleist C. Eckstein V. Sellner L. Müller-Tidow C. Dreger P. Schmitt M. Schmitt A. Dual effects of cyclooxygenase inhibitors in combination with CD19. CAR-T cell immunotherapy. Front. Immunol. 2021 12 670088 10.3389/fimmu.2021.670088 34122428
    [Google Scholar]
  73. Irie T. Tsujii M. Tsuji S. Yoshio T. Ishii S. Shinzaki S. Egawa S. Kakiuchi Y. Nishida T. Yasumaru M. Iijima H. Murata H. Takehara T. Kawano S. Hayashi N. Synergistic antitumor effects of celecoxib with 5‐fluorouracil depend on IFN‐γ. Int. J. Cancer 2007 121 4 878 883 10.1002/ijc.22720 17450522
    [Google Scholar]
  74. Shishodia S. Koul D. Aggarwal B.B. Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates TNF-induced NF-κ B activation through inhibition of activation of I κ B α kinase and Akt in human non-small cell lung carcinoma: Correlation with suppression of COX-2 synthesis. J. Immunol. 2004 173 3 2011 2022 10.4049/jimmunol.173.3.2011 15265936
    [Google Scholar]
  75. Lacher S.B. Dörr J. Almeida D.G.P. Hönninger J. Bayerl F. Hirschberger A. Pedde A.M. Meiser P. Ramsauer L. Rudolph T.J. Spranger N. Morotti M. Grimm A.J. Jarosch S. Oner A. Gregor L. Lesch S. Michaelides S. Fertig L. Briukhovetska D. Majed L. Stock S. Busch D.H. Buchholz V.R. Knolle P.A. Zehn D. Laniti D.D. Kobold S. Böttcher J.P. PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells. Nature 2024 629 8011 417 425 10.1038/s41586‑024‑07254‑x 38658748
    [Google Scholar]
  76. Wu Y. Chen W. Xu Z.P. Gu W. PD-L1 distribution and perspective for cancer immunotherapy—blockade, knockdown, or inhibition. Front. Immunol. 2022 10 2022 10.3389/fimmu.2019.02022 31507611
    [Google Scholar]
  77. Cecil D.L. Gad E.A. Corulli L.R. Drovetto N. Lubet R.A. Disis M.L. COX-2 inhibitors decrease expression of PD-L1 in colon tumors and increase the influx of type I tumor-infiltrating lymphocytes. Cancer Prev. Res. 2022 15 4 225 231 10.1158/1940‑6207.CAPR‑21‑0227 34987061
    [Google Scholar]
  78. Botti G. Fratangelo F. Cerrone M. Liguori G. Cantile M. Anniciello A.M. Scala S. D’Alterio C. Trimarco C. Ianaro A. Cirino G. Caracò C. Colombino M. Palmieri G. Pepe S. Ascierto P.A. Sabbatino F. Scognamiglio G. COX-2 expression positively correlates with PD-L1 expression in human melanoma cells. J. Transl. Med. 2017 15 1 46 10.1186/s12967‑017‑1150‑7 28231855
    [Google Scholar]
/content/journals/ctmc/10.2174/0115680266364293250613090952
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Carbonic Anhydrase IX and Cyclooxygenase-2 Regulation in Renal Cell Carcinoma and Impact on Therapeutic Efficiency of Anti-CAIX CAR T cells
Bentham Science Publishers ; https://doi.org/10.2174/0115680266364293250613090952
/content/journals/ctmc/10.2174/0115680266364293250613090952
/content/journals/ctmc/10.2174/0115680266364293250613090952
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  • Article Type:     Research Article
Keywords: COX-2 ; celecoxib ; RCC ; anti-inflammatory ; analgesic ; COX-2 inhibitors ; CAIX immunotherapy ; CAR T cells

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