Decrease of Tumor-infiltrating Regulatory T Cells Using Pentoxifylline: An Ex Vivo Analysis in Triple-negative Breast Cancer Mouse Model
-
Mohammad Hossein Kazemi
,
Mahdieh Shokrollahi Barough
,
Alireza Ghanavatinejad
,
Zahra Momeni-Varposhti
,
Samaneh Khorrami
,
Behnam Sadeghi
,
Reza Falak
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive type of BC with the highest percentage of tumor-infiltrating lymphocytes (TILs). Hence, TIL therapy is considered a promising approach to target TNBC. Depletion of regulatory T cells (Tregs) in TILs can improve the antitumor function of TIL therapy. Pentoxifylline (PTXF) is a xanthine derivative that can modulate the nuclear factor kappa B (NF-κB) signaling and probably affect the Treg proportion in TILs. We aimed to evaluate the ex vivo effect of PTXF on the proportion of Treg cells in the TILs derived from a mouse model of TNBC.
The 4T1 cells were inoculated subcutaneously to BALB/c mice to induce TNBC. TILs were isolated from tumor tissue by enzymatic digestion and cultured alone or with 4T1 cells for 24, 48, and 72 h in the presence of interleukin (IL)-2 and different concentrations of PTXF. The toxicity of PTXF and its effects on Tregs proportion as well as cytokine production was evaluated using MTT assay, flow cytometry, and ELISA, respectively.
PTXF had no significant impact on the viability of TILs. Both 500 and 1000 mg/mL of PTXF decreased the proportion of Tregs in a dose-dependent manner. The level of interferon-g and tumor growth factor-b in TILs supernatant was increased and decreased, respectively.
Our data suggest that ex vivo treatment of TILs with pentoxifylline could decrease the proportion of Tregs in the conventional IL-2-mediated TIL expansion and change the cytokine balance of TILs in favor of antitumor immune response.
1. Barzaman K, Karami J, Zarei Z, Hosseinzadeh A, Kazemi MH, Moradi-Kalbolandi S, et al. Breast cancer: Biology, biomarkers, and treatments. Int Immunopharmacol. 2020;84:106535.
2. Tang Y, Wang Y, Kiani MF, Wang B. Classification, treatment strategy, and associated drug resistance in breast cancer. Clin Breast Cancer. 2016;16(5):335–43.
3. Lee K-L, Kuo Y-C, Ho Y-S, Huang Y-H. Triple-negative breast cancer: Current understanding and future therapeutic breakthrough targeting cancer stemness. Cancers (Basel). 2019;11(9):1334.
4. Van der Spek YM, Kroep JR, Tollenaar R, Mesker WE. Chemotherapy resistance and stromal targets in breast cancer treatment: a review. Mol Biol Rep. 2020;1–9.
5. Barzaman K, Moradi-Kalbolandi S, Hosseinzadeh A, Kazemi MH, Khorramdelazad H, Safari E, et al. Breast cancer immunotherapy: Current and novel approaches. Int Immunopharmacol. 2021;98:107886.
6. Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013;31(7):860–7.
7. Kurozumi S, Matsumoto H, Kurosumi M, Inoue K, Fujii T, Horiguchi J, et al. Prognostic significance of tumour‑infiltrating lymphocytes for oestrogen receptor‑negative breast cancer without lymph node metastasis. Oncol Lett. 2019;17(3):2647–56.
8. Gao G, Wang Z, Qu X, Zhang Z. Prognostic value of tumor-infiltrating lymphocytes in patients with triple-negative breast cancer: a systematic review and meta-analysis. BMC Cancer. 2020;20(1):1–15.
9. Tsuyuguchi I, Shiratsuchi H, Fukuoka M. T-lymphocyte subsets in primary lung cancer. Jpn J Clin Oncol. 1987;17(1):13–7.
10. Underwood JCE. Lymphoreticular infiltration in human tumours: Prognostic and biological implications: A review. Br J Cancer. 1974;30(6):538–48.
11. Ali HR, Provenzano E, Dawson S-J, Blows FM, Liu B, Shah M, et al. Association between CD8+ T-cell infiltration and breast cancer survival in 12 439 patients. Ann Oncol. 2014;25(8):1536–43.
12. Schwartzentruber DJ, Topalian SL, Mancini M, Rosenberg SA. Specific release of granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, and IFN-gamma by human tumor-infiltrating lymphocytes after autologous tumor stimulation. J Immunol. 1991;146(10):3674–81.
13. Schwartzentruber DJ, Solomon D, Rosenberg SA, Topalian SL. Characterization of lymphocytes infiltrating human breast cancer: specific immune reactivity detected by measuring cytokine secretion. J Immunother. 1992;12(1):1–12.
14. Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: Results from the FinHER trial. Ann Oncol. 2014;25(8):1544–50.
15. Yamaguchi R, Tanaka M, Yano A, Gary MT, Yamaguchi M, Koura K, et al. Tumor-infiltrating lymphocytes are important pathologic predictors for neoadjuvant chemotherapy in patients with breast cancer. Hum Pathol. 2012;43(10):1688–94.
16. Shou J, Zhang Z, Lai Y, Chen Z, Huang J. Worse outcome in breast cancer with higher tumor-infiltrating FOXP3+ Tregs: A systematic review and meta-analysis. BMC Cancer. 2016;16(1).
17. Xu L, Xu W, Qiu S, Xiong S. Enrichment of CCR6+Foxp3+ regulatory T cells in the tumor mass correlates with impaired CD8+ T cell function and poor prognosis of breast cancer. Clin Immunol. 2010;135(3):466–75.
18. Grinberg-Bleyer Y, Oh H, Desrichard A, Bhatt DM, Caron R, Chan TA, et al. NF-κB c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer. Cell. 2017;170(6):1096–1108.e13.
19. Li A, Jacks T. Driving Rel-iant Tregs toward an Identity Crisis. Immunity. 2017;47(3):391–3.
20. Gilmore TD, Gerondakis S. The c-Rel Transcription Factor in Development and Disease. Genes Cancer. 2011;2(7):695–711.
21. Wang W, Tam WF, Hughes CCW, Rath S, Sen R. c-Rel is a target of pentoxifylline-mediated inhibition of T lymphocyte activation. Immunity. 1997;6(2):165–74.
22. Salhiyyah K, Forster R, Senanayake E, Abdel-Hadi M, Booth A, Michaels JA. Pentoxifylline for intermittent claudication. In: Cochrane Database of Systematic Reviews [Internet]. 2015. Available from: http://doi.wiley.com/10.1002/14651858.CD005262.pub3
23. Combaret L, Rallière C, Taillandier D, Tanaka K, Attaix D. Manipulation of the ubiquitin-proteasome pathway in cachexia: pentoxifylline suppresses the activation of 20S and 26S proteasomes in muscles from tumor-bearing rats. Mol Biol Rep. 1999;26(1):95–101.
24. Stevanović S, Helman SR, Wunderlich JR, Langhan MM, Doran SL, Kwong MLM, et al. A phase II study of tumor-infiltrating lymphocyte therapy for human papillomavirus–associated epithelial cancers. Clin Cancer Res. 2019;25(5):1486–93.
25. Andersen R, Donia M, Ellebaek E, Borch TH, Kongsted P, Iversen TZ, et al. Long-Lasting complete responses in patients with metastatic melanoma after adoptive cell therapy with tumor-infiltrating lymphocytes and an attenuated il2 regimen. Clin Cancer Res. 2016;22(15):3734–45.
26. Ben-Avi R, Farhi R, Ben-Nun A, Gorodner M, Greenberg E, Markel G, et al. Establishment of adoptive cell therapy with tumor infiltrating lymphocytes for non-small cell lung cancer patients. Cancer Immunol Immunother. 2018;67(8):1221–30.
27. Assadipour Y, Zacharakis N, Crystal JS, Prickett TD, Gartner JJ, Somerville RPT, et al. Characterization of an immunogenic mutation in a patient with metastatic triple-negative breast cancer. Clin Cancer Res. 2017;23(15):4347–53.
28. Hirai I, Funakoshi T, Kamijuku H, Fukuda K, Mori M, Sakurai M, et al. Adoptive cell therapy using tumor‐infiltrating lymphocytes for melanoma refractory to immune‐checkpoint inhibitors. Cancer science. 2021;112(8):3163-3172..
29. Knutson KL, Dang Y, Lu H, Lukas J, Almand B, Gad E, et al. IL-2 immunotoxin therapy modulates tumor-associated regulatory T cells and leads to lasting immune-mediated rejection of breast cancers in neu-transgenic mice. J Immunol. 2006;177(1):84–91.
30. Shang B, Liu Y, Jiang S, Liu Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep. 2015;5:15179.
31. Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer. 2010;127(4):759–67.
32. Nguyen LT, Saibil SD, Sotov V, Le MX, Khoja L, Ghazarian D, et al. Phase II clinical trial of adoptive cell therapy for patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and low-dose interleukin-2. Cancer Immunol Immunother. 2019;68(5):773–85.
33. Jiang T, Zhou C, Ren S. Role of IL-2 in cancer immunotherapy. Oncoimmunology. 2016;5(6):e1163462.
34. Oh H, Grinberg-Bleyer Y, Liao W, Maloney D, Wang P, Wu Z, et al. An NF-κB transcription-factor-dependent lineage-specific transcriptional program promotes regulatory T cell identity and function. Immunity. 2017;47(3):450–65.
35. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science (80- ). 2003;299(5609):1057–61.
36. Georgiev P, Charbonnier L-M, Chatila TA. Regulatory T cells: the many faces of Foxp3. J Clin Immunol. 2019;39(7):623–40.
37. Ruan Q, Kameswaran V, Tone Y, Li L, Liou H-C, Greene MI, et al. Development of Foxp3+ regulatory T cells is driven by the c-Rel enhanceosome. Immunity. 2009;31(6):932–40.
38. Isomura I, Palmer S, Grumont RJ, Bunting K, Hoyne G, Wilkinson N, et al. c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells. J Exp Med [Internet]. 2009;206(13):3001–14. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2806473&tool=pmcentrez&rendertype=abstract
39. Bravo-Cuellar A, Hernández-Flores G, Lerma-Díaz JM, Domínguez-Rodríguez JR, Jave-Suárez LF, De Célis-Carrillo R, et al. Pentoxifylline and the proteasome inhibitor MG132 induce apoptosis in human leukemia U937 cells through a decrease in the expression of Bcl-2 and Bcl-XL and phosphorylation of p65. J Biomed Sci. 2013;20(1):1–13.
40. Kamran MZ, Gude RP. Preclinical evaluation of the antimetastatic efficacy of Pentoxifylline on A375 human melanoma cell line. Biomed Pharmacother. 2012;66(8):617–26.
41. Nidhyanandan S, Boreddy TS, Chandrasekhar KB, Reddy ND, Kulkarni NM, Narayanan S. Phosphodiesterase inhibitor, pentoxifylline enhances anticancer activity of histone deacetylase inhibitor, MS-275 in human breast cancer in vitro and in vivo. Eur J Pharmacol. 2015;764:508–19.
42. Rott O, Cash E, Fleischer B. Phosphodiesterase inhibitor pentoxifylline, a selective suppressor of T helper type 1‐but not type 2‐associated lymphokine production, prevents induction of experimental autoimmune encephalomyelitis in Lewis rats. Eur J Immunol. 1993;23(8):1745–51.
43. Coon ME, Diegel M, Leshinsky N, Klaus SJ. Selective pharmacologic inhibition of murine and human IL-12-dependent Th1 differentiation and IL-12 signaling. J Immunol. 1999;163(12):6567–74.
44. Kadoshima-Yamaoka K, Murakawa M, Goto M, Tanaka Y, Inoue H, Murafuji H, et al. ASB16165, a novel inhibitor for phosphodiesterase 7A (PDE7A), suppresses IL-12-induced IFN-γ production by mouse activated T lymphocytes. Immunol Lett. 2009;122(2):193–7.
45. Suresh R, Vig M, Bhatia S, Goodspeed EPB, John B, Kandpal U, et al. Pentoxifylline functions as an adjuvant in vivo to enhance T cell immune responses by inhibiting activation-induced death. J Immunol. 2002;169(8):4262–72.
46. Kummari E, Gibbs A, Riggs C, Fellman C, Stokes J, Thomason J, et al. Effects of pentoxifylline on whole blood IL‐2 and IFN‐gamma gene expression in normal dogs. Vet Med Sci. 2020;6(1):19–24.
47. Zakeri Z, Davarian A, Fazeli SA, Sandoughi M, Shahbakhsh S, Shahbakhsh Y, et al. Pentoxifylline as a new adjunctive therapy in ankylosing spondylitis: A randomized clinical trial. Rheumatol Res. 2017;2(3):91–6.
48. Cotter TG, Kamboj AK, Hicks SB, Tremaine WJ, Loftus Jr E V, Pardi DS. Case report: Pentoxifylline treatment in microscopic colitis. Medicine (Baltimore). 2017;96(46):112-9.
49. Brito G, Dourado M, Guimarães LH, Meireles E, Schriefer A, de Carvalho EM, et al. Oral Pentoxifylline Associated with Pentavalent Antimony: A Randomized Trial for Cutaneous Leishmaniasis. Am J Trop Med Hyg. 2017;96(5):1155–9.
50. Rodríguez-Morán M, Guerrero-Romero F. Efficacy of pentoxifylline in the management of microalbuminuria in patients with diabetes. Curr Diabetes Rev. 2008;4(1):55–62.
51. Fredholm BB, Persson CGA. Xanthine derivatives as adenosine receptor antagonists. Eur J Pharmacol. 1982;81(4):673–6.
52. Ghosh S, Grinberg-bleyer Y. Use of pentoxifylline with immune checkpoint-blockade therapies for the treatment of melanoma. Google Patents; 2017.
53. Kazemi MH, Najafi A, Karami J, Ghazizadeh F, Yousefi H, Falak R, et al. Immune and metabolic checkpoints blockade: Dual wielding against tumors. Int Immunopharmacol. 2021;94(15):107461.
2. Tang Y, Wang Y, Kiani MF, Wang B. Classification, treatment strategy, and associated drug resistance in breast cancer. Clin Breast Cancer. 2016;16(5):335–43.
3. Lee K-L, Kuo Y-C, Ho Y-S, Huang Y-H. Triple-negative breast cancer: Current understanding and future therapeutic breakthrough targeting cancer stemness. Cancers (Basel). 2019;11(9):1334.
4. Van der Spek YM, Kroep JR, Tollenaar R, Mesker WE. Chemotherapy resistance and stromal targets in breast cancer treatment: a review. Mol Biol Rep. 2020;1–9.
5. Barzaman K, Moradi-Kalbolandi S, Hosseinzadeh A, Kazemi MH, Khorramdelazad H, Safari E, et al. Breast cancer immunotherapy: Current and novel approaches. Int Immunopharmacol. 2021;98:107886.
6. Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013;31(7):860–7.
7. Kurozumi S, Matsumoto H, Kurosumi M, Inoue K, Fujii T, Horiguchi J, et al. Prognostic significance of tumour‑infiltrating lymphocytes for oestrogen receptor‑negative breast cancer without lymph node metastasis. Oncol Lett. 2019;17(3):2647–56.
8. Gao G, Wang Z, Qu X, Zhang Z. Prognostic value of tumor-infiltrating lymphocytes in patients with triple-negative breast cancer: a systematic review and meta-analysis. BMC Cancer. 2020;20(1):1–15.
9. Tsuyuguchi I, Shiratsuchi H, Fukuoka M. T-lymphocyte subsets in primary lung cancer. Jpn J Clin Oncol. 1987;17(1):13–7.
10. Underwood JCE. Lymphoreticular infiltration in human tumours: Prognostic and biological implications: A review. Br J Cancer. 1974;30(6):538–48.
11. Ali HR, Provenzano E, Dawson S-J, Blows FM, Liu B, Shah M, et al. Association between CD8+ T-cell infiltration and breast cancer survival in 12 439 patients. Ann Oncol. 2014;25(8):1536–43.
12. Schwartzentruber DJ, Topalian SL, Mancini M, Rosenberg SA. Specific release of granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, and IFN-gamma by human tumor-infiltrating lymphocytes after autologous tumor stimulation. J Immunol. 1991;146(10):3674–81.
13. Schwartzentruber DJ, Solomon D, Rosenberg SA, Topalian SL. Characterization of lymphocytes infiltrating human breast cancer: specific immune reactivity detected by measuring cytokine secretion. J Immunother. 1992;12(1):1–12.
14. Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: Results from the FinHER trial. Ann Oncol. 2014;25(8):1544–50.
15. Yamaguchi R, Tanaka M, Yano A, Gary MT, Yamaguchi M, Koura K, et al. Tumor-infiltrating lymphocytes are important pathologic predictors for neoadjuvant chemotherapy in patients with breast cancer. Hum Pathol. 2012;43(10):1688–94.
16. Shou J, Zhang Z, Lai Y, Chen Z, Huang J. Worse outcome in breast cancer with higher tumor-infiltrating FOXP3+ Tregs: A systematic review and meta-analysis. BMC Cancer. 2016;16(1).
17. Xu L, Xu W, Qiu S, Xiong S. Enrichment of CCR6+Foxp3+ regulatory T cells in the tumor mass correlates with impaired CD8+ T cell function and poor prognosis of breast cancer. Clin Immunol. 2010;135(3):466–75.
18. Grinberg-Bleyer Y, Oh H, Desrichard A, Bhatt DM, Caron R, Chan TA, et al. NF-κB c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer. Cell. 2017;170(6):1096–1108.e13.
19. Li A, Jacks T. Driving Rel-iant Tregs toward an Identity Crisis. Immunity. 2017;47(3):391–3.
20. Gilmore TD, Gerondakis S. The c-Rel Transcription Factor in Development and Disease. Genes Cancer. 2011;2(7):695–711.
21. Wang W, Tam WF, Hughes CCW, Rath S, Sen R. c-Rel is a target of pentoxifylline-mediated inhibition of T lymphocyte activation. Immunity. 1997;6(2):165–74.
22. Salhiyyah K, Forster R, Senanayake E, Abdel-Hadi M, Booth A, Michaels JA. Pentoxifylline for intermittent claudication. In: Cochrane Database of Systematic Reviews [Internet]. 2015. Available from: http://doi.wiley.com/10.1002/14651858.CD005262.pub3
23. Combaret L, Rallière C, Taillandier D, Tanaka K, Attaix D. Manipulation of the ubiquitin-proteasome pathway in cachexia: pentoxifylline suppresses the activation of 20S and 26S proteasomes in muscles from tumor-bearing rats. Mol Biol Rep. 1999;26(1):95–101.
24. Stevanović S, Helman SR, Wunderlich JR, Langhan MM, Doran SL, Kwong MLM, et al. A phase II study of tumor-infiltrating lymphocyte therapy for human papillomavirus–associated epithelial cancers. Clin Cancer Res. 2019;25(5):1486–93.
25. Andersen R, Donia M, Ellebaek E, Borch TH, Kongsted P, Iversen TZ, et al. Long-Lasting complete responses in patients with metastatic melanoma after adoptive cell therapy with tumor-infiltrating lymphocytes and an attenuated il2 regimen. Clin Cancer Res. 2016;22(15):3734–45.
26. Ben-Avi R, Farhi R, Ben-Nun A, Gorodner M, Greenberg E, Markel G, et al. Establishment of adoptive cell therapy with tumor infiltrating lymphocytes for non-small cell lung cancer patients. Cancer Immunol Immunother. 2018;67(8):1221–30.
27. Assadipour Y, Zacharakis N, Crystal JS, Prickett TD, Gartner JJ, Somerville RPT, et al. Characterization of an immunogenic mutation in a patient with metastatic triple-negative breast cancer. Clin Cancer Res. 2017;23(15):4347–53.
28. Hirai I, Funakoshi T, Kamijuku H, Fukuda K, Mori M, Sakurai M, et al. Adoptive cell therapy using tumor‐infiltrating lymphocytes for melanoma refractory to immune‐checkpoint inhibitors. Cancer science. 2021;112(8):3163-3172..
29. Knutson KL, Dang Y, Lu H, Lukas J, Almand B, Gad E, et al. IL-2 immunotoxin therapy modulates tumor-associated regulatory T cells and leads to lasting immune-mediated rejection of breast cancers in neu-transgenic mice. J Immunol. 2006;177(1):84–91.
30. Shang B, Liu Y, Jiang S, Liu Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep. 2015;5:15179.
31. Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer. 2010;127(4):759–67.
32. Nguyen LT, Saibil SD, Sotov V, Le MX, Khoja L, Ghazarian D, et al. Phase II clinical trial of adoptive cell therapy for patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and low-dose interleukin-2. Cancer Immunol Immunother. 2019;68(5):773–85.
33. Jiang T, Zhou C, Ren S. Role of IL-2 in cancer immunotherapy. Oncoimmunology. 2016;5(6):e1163462.
34. Oh H, Grinberg-Bleyer Y, Liao W, Maloney D, Wang P, Wu Z, et al. An NF-κB transcription-factor-dependent lineage-specific transcriptional program promotes regulatory T cell identity and function. Immunity. 2017;47(3):450–65.
35. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science (80- ). 2003;299(5609):1057–61.
36. Georgiev P, Charbonnier L-M, Chatila TA. Regulatory T cells: the many faces of Foxp3. J Clin Immunol. 2019;39(7):623–40.
37. Ruan Q, Kameswaran V, Tone Y, Li L, Liou H-C, Greene MI, et al. Development of Foxp3+ regulatory T cells is driven by the c-Rel enhanceosome. Immunity. 2009;31(6):932–40.
38. Isomura I, Palmer S, Grumont RJ, Bunting K, Hoyne G, Wilkinson N, et al. c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells. J Exp Med [Internet]. 2009;206(13):3001–14. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2806473&tool=pmcentrez&rendertype=abstract
39. Bravo-Cuellar A, Hernández-Flores G, Lerma-Díaz JM, Domínguez-Rodríguez JR, Jave-Suárez LF, De Célis-Carrillo R, et al. Pentoxifylline and the proteasome inhibitor MG132 induce apoptosis in human leukemia U937 cells through a decrease in the expression of Bcl-2 and Bcl-XL and phosphorylation of p65. J Biomed Sci. 2013;20(1):1–13.
40. Kamran MZ, Gude RP. Preclinical evaluation of the antimetastatic efficacy of Pentoxifylline on A375 human melanoma cell line. Biomed Pharmacother. 2012;66(8):617–26.
41. Nidhyanandan S, Boreddy TS, Chandrasekhar KB, Reddy ND, Kulkarni NM, Narayanan S. Phosphodiesterase inhibitor, pentoxifylline enhances anticancer activity of histone deacetylase inhibitor, MS-275 in human breast cancer in vitro and in vivo. Eur J Pharmacol. 2015;764:508–19.
42. Rott O, Cash E, Fleischer B. Phosphodiesterase inhibitor pentoxifylline, a selective suppressor of T helper type 1‐but not type 2‐associated lymphokine production, prevents induction of experimental autoimmune encephalomyelitis in Lewis rats. Eur J Immunol. 1993;23(8):1745–51.
43. Coon ME, Diegel M, Leshinsky N, Klaus SJ. Selective pharmacologic inhibition of murine and human IL-12-dependent Th1 differentiation and IL-12 signaling. J Immunol. 1999;163(12):6567–74.
44. Kadoshima-Yamaoka K, Murakawa M, Goto M, Tanaka Y, Inoue H, Murafuji H, et al. ASB16165, a novel inhibitor for phosphodiesterase 7A (PDE7A), suppresses IL-12-induced IFN-γ production by mouse activated T lymphocytes. Immunol Lett. 2009;122(2):193–7.
45. Suresh R, Vig M, Bhatia S, Goodspeed EPB, John B, Kandpal U, et al. Pentoxifylline functions as an adjuvant in vivo to enhance T cell immune responses by inhibiting activation-induced death. J Immunol. 2002;169(8):4262–72.
46. Kummari E, Gibbs A, Riggs C, Fellman C, Stokes J, Thomason J, et al. Effects of pentoxifylline on whole blood IL‐2 and IFN‐gamma gene expression in normal dogs. Vet Med Sci. 2020;6(1):19–24.
47. Zakeri Z, Davarian A, Fazeli SA, Sandoughi M, Shahbakhsh S, Shahbakhsh Y, et al. Pentoxifylline as a new adjunctive therapy in ankylosing spondylitis: A randomized clinical trial. Rheumatol Res. 2017;2(3):91–6.
48. Cotter TG, Kamboj AK, Hicks SB, Tremaine WJ, Loftus Jr E V, Pardi DS. Case report: Pentoxifylline treatment in microscopic colitis. Medicine (Baltimore). 2017;96(46):112-9.
49. Brito G, Dourado M, Guimarães LH, Meireles E, Schriefer A, de Carvalho EM, et al. Oral Pentoxifylline Associated with Pentavalent Antimony: A Randomized Trial for Cutaneous Leishmaniasis. Am J Trop Med Hyg. 2017;96(5):1155–9.
50. Rodríguez-Morán M, Guerrero-Romero F. Efficacy of pentoxifylline in the management of microalbuminuria in patients with diabetes. Curr Diabetes Rev. 2008;4(1):55–62.
51. Fredholm BB, Persson CGA. Xanthine derivatives as adenosine receptor antagonists. Eur J Pharmacol. 1982;81(4):673–6.
52. Ghosh S, Grinberg-bleyer Y. Use of pentoxifylline with immune checkpoint-blockade therapies for the treatment of melanoma. Google Patents; 2017.
53. Kazemi MH, Najafi A, Karami J, Ghazizadeh F, Yousefi H, Falak R, et al. Immune and metabolic checkpoints blockade: Dual wielding against tumors. Int Immunopharmacol. 2021;94(15):107461.
| Files | ||
| Issue | Vol 21 No 2 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v21i2.9224 | |
| Keywords | ||
| Breast neoplasms Pentoxifylline Regulatory T-lymphocytes Tumor-infiltrating lymphocytes | ||
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How to Cite
1.
Kazemi MH, Shokrollahi Barough M, Ghanavatinejad A, Momeni-Varposhti Z, Khorrami S, Sadeghi B, Falak R. Decrease of Tumor-infiltrating Regulatory T Cells Using Pentoxifylline: An Ex Vivo Analysis in Triple-negative Breast Cancer Mouse Model. Iran J Allergy Asthma Immunol. 2022;21(2):167-177.
