MicroRNA-124 Enhances T Cells Functions by Manipulating the Lactic Acid Metabolism of Tumor Cells
-
Mohammad Khakpoor-Koosheh
,
Hosein Rostamian
,
Elham Masoumi
,
Leila Jafarzadeh
,
Keyvan Fallah-Mehrjardi
,
Mohammad Javad Tavassolifar
,
Farshid Noorbakhsh
,
Hamid Reza Mirzaei
,
jamshid Hadjati
,
Nima Rezaei
Abstract
High production of lactic acid is a common feature of various tumors. Lactic acid is an immunosuppressive molecule with crucial roles in tumor cells' immune escape, which could largely be attributed to its negative effects on the T cells present in the tumor microenvironment (TME). Strategies that decrease the glycolysis rate of tumor cells could enhance immunosurveillance and limit tumor growth. Pyruvate kinase M2 (PKM2) is a key enzyme in the glycolysis pathway, and it plays a vital role in lactic acid buildup in the TME. MicroRNA (miR)-124 has been shown to be able to decrease tumor cell lactic acid synthesis indirectly by reducing PKM2 levels.
In this study, we first overexpressed miR-124 in the tumor cells and evaluated its effects on the PKM2 expression and lactic acid production of the tumor cells using quantitative real-time polymerase chain reaction (qRT-PCR) and spectrophotometry, respectively. Then, we cocultured miR-124–treated tumor cells with T cells to investigate the effects of miR-124 overexpression on T cell proliferation, cytokine production, and apoptosis.
Our results demonstrated that miR-124 overexpression could significantly reduce the amount of lactic acid produced by tumor cells by manipulating their glucose metabolism, which led to the augmented proliferation and IFN-γ production of T cells. Moreover, it rescued T cells from lactic acid-induced apoptosis.
Our data suggest that lactic acid is a hindering factor for T-cell–based immunotherapies; however, manipulating tumor cells' metabolism via miR-124 could be a promising way to improve antitumor responses of T cells.
1. Maus MV, Grupp SA, Porter DL, June CHJB. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood. 2014;123(17):2625-35.
2. Melero I, Rouzaut A, Motz GT, Coukos GJCd. T-cell and NK-cell infiltration into solid tumors: a key limiting factor for efficacious cancer immunotherapy. Cancer Discov. 2014;4(5):522-6.
3. Labani-Motlagh A, Ashja-Mahdavi M, Loskog AJFiI. The tumor microenvironment: A milieu hindering and obstructing antitumor immune responses. Front Immunol. 2020;11:940.
4. Fallah-Mehrjardi K, Mirzaei HR, Masoumi E, Jafarzadeh L, Rostamian H, Khakpoor-Koosheh M, et al. Pharmacological targeting of immune checkpoint A2aR improves function of anti-CD19 CAR T cells in vitro. Immunol Lett. 2020;223(26):44-52.
5. Rostamian H, Fallah-Mehrjardi K, Khakpoor-Koosheh M, Pawelek JM, Hadjati J, Brown CE, et al. A metabolic switch to memory CAR T cells: Implications for cancer treatment. Cancer Lett. 2021;500(14):107-18.
6. Ward PS, Thompson CBJCc. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer cell. 2012;21(3):297-308.
7. Corbet C, Feron OJNRC. Tumour acidosis: from the passenger to the driver's seat. Nat Rev Cancer. 2017;17(10):577.
8. Pérez-Tomás R, Pérez-Guillén IJC. Lactate in the Tumor Microenvironment: An Essential Molecule in Cancer Progression and Treatment. Cancers (Basel). 2020;12(11):3244.
9. Balgi AD, Diering GH, Donohue E, Lam KK, Fonseca BD, Zimmerman C, et al. Regulation of mTORC1 signaling by pH. PloS one. 2011;6(6):e21549.
10. Romero-Garcia S, Moreno-Altamirano MMB, Prado-Garcia H, Sánchez-García FJJFii. Lactate contribution to the tumor microenvironment: mechanisms, effects on immune cells and therapeutic relevance. Front Immunol. 2016;7(2):52.
11. Ganapathy-Kanniappan S, Geschwind J-FHJMc. Tumor glycolysis as a target for cancer therapy: progress and prospects. Mol Cancer. 2013;12(1):1-11.
12. Clower CV, Chatterjee D, Wang Z, Cantley LC, Vander Heiden MG, Krainer ARJPotNAoS. The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proc Natl Acad Sci. 2010;107(5):1894-9.
13. Zahra K, Dey T, Mishra SP, Pandey UJFio. Pyruvate kinase M2 and cancer: the role of PKM2 in promoting tumorigenesis. Front Oncol. 2020;10:159.
14. Peng Y, Croce CMJSt, therapy t. The role of MicroRNAs in human cancer. Signal transduction and targeted therapy. 2016;1(1):1-9.
15. Jia X, Wang X, Guo X, Ji J, Lou G, Zhao J, et al. MicroRNA‐124: an emerging therapeutic target in cancer. Cancer Medicine. 2019;8(12):5638-50.
16. Sun Y, Zhao X, Zhou Y, Hu YJOr. miR-124, miR-137 and miR-340 regulate colorectal cancer growth via inhibition of the Warburg effect. Oncology reports. 2012;28(4):1346-52.
17. Taniguchi K, Sugito N, Kumazaki M, Shinohara H, Yamada N, Nakagawa Y, et al. MicroRNA-124 inhibits cancer cell growth through PTB1/PKM1/PKM2 feedback cascade in colorectal cancer. Cancer Lett. 2015;363(1):17-27.
18. Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundfør K, Rofstad EK, et al. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. 2000;60(4):916-21.
19. Walenta S, Salameh A, Lyng H, Evensen JF, Mitze M, Rofstad EK, et al. Correlation of high lactate levels in head and neck tumors with incidence of metastasis. 1997;150(2):409.
20. Brizel DM, Schroeder T, Scher RL, Walenta S, Clough RW, Dewhirst MW, et al. Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. 2001;51(2):349-53.
21. Yokota H, Guo J, Matoba M, Higashi K, Tonami H, Nagao YJJoMRIAOJotISfMRiM. Lactate, choline, and creatine levels measured by vitro 1H‐MRS as prognostic parameters in patients with non‐small‐cell lung cancer. 2007;25(5):992-9.
22. Qian J, Gong Z-c, Zhang Y-n, Wu H-h, Zhao J, Wang L-t, et al. Lactic acid promotes metastatic niche formation in bone metastasis of colorectal cancer. Cell Commun Signal. 2021;19(1):1-15.
23. Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 2016;24(5):657-71.
24. Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, et al. Inhibitory effect of tumor cell–derived lactic acid on human T cells. 2007;109(9):3812-9.
25. Pilon-Thomas S, Kodumudi KN, El-Kenawi AE, Russell S, Weber AM, Luddy K, et al. Neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer Res. 2016;76(6):1381-90.
26. Quinn III WJ, Jiao J, TeSlaa T, Stadanlick J, Wang Z, Wang L, et al. Lactate limits T cell proliferation via the NAD (H) redox state. Cell Rep. 2020;33(11):108500.
27. Lim AR, Rathmell WK, Rathmell JCJE. The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy. Elife. 2020;9:e55185.
28. Calcinotto A, Filipazzi P, Grioni M, Iero M, De Milito A, Ricupito A, et al. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res. 2012;72(11):2746-56.
29. Cascone T, McKenzie JA, Mbofung RM, Punt S, Wang Z, Xu C, et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab. 2018;27(5):977-87. e4.
30. Renner K, Bruss C, Schnell A, Koehl G, Becker HM, Fante M, et al. Restricting glycolysis preserves T cell effector functions and augments checkpoint therapy. Cell Rep. 2019;29(1):135-50. e9.
31. Luo W, Semenza GLJTiE, Metabolism. Emerging roles of PKM2 in cell metabolism and cancer progression. Trends in Endocrinology & Metabolism. 2012;23(11):560-6.
32. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. 2008;452(7184):230-3.
33. Qiu Z, Guo W, Wang Q, Chen Z, Huang S, Zhao F, et al. MicroRNA-124 reduces the pentose phosphate pathway and proliferation by targeting PRPS1 and RPIA mRNAs in human colorectal cancer cells. Gastroenterology. 2015;149(6):1587-98. e11.
34. Taniguchi K, Ito Y, Sugito N, Kumazaki M, Shinohara H, Yamada N, et al. Organ-specific PTB1-associated microRNAs determine expression of pyruvate kinase isoforms. Sci Rep. 2015;5(1):1-8.
35. Rundqvist H, Veliça P, Barbieri L, Gameiro P, Cunha PP, Gojkovic M, et al. Lactate potentiates differentiation and expansion of cytotoxic T cells. 2019.
36. Wen J, Cheng S, Zhang Y, Wang R, Xu J, Ling Z, et al. Lactate anions participate in T cell cytokine production and function. Sci China Life Sci. 2021:1-11.
37. Zhang Y, Wen J, Sun B. Lactate is critical for cytokines production of T cell after TCR activation. Am Assoc Immnol. 2020;204(1 Supplement):240.3.
38. Polanczyk MJ, Walker E, Haley D, Guerrouahen BS, Akporiaye ETJJotm. Blockade of TGF-β signaling to enhance the antitumor response is accompanied by dysregulation of the functional activity of CD4+ CD25+ Foxp3+ and CD4+ CD25− Foxp3+ T cells. J Transl Med. 2019;17(1):1-12.
39. Masoumi E, Jafarzadeh L, Mirzaei HR, Alishah K, Fallah-Mehrjardi K, Rostamian H, et al. Genetic and pharmacological targeting of A2a receptor improves function of anti-mesothelin CAR T cells. 2020;39(1):1-12.
40. Kanchan RK, Perumal N, Atri P, Chirravuri Venkata R, Thapa I, Klinkebiel DL, et al. MiR‐1253 exerts tumor‐suppressive effects in medulloblastoma via inhibition of CDK6 and CD276 (B7‐H3). Brain Pathol. 2020;30(4):732-45.
41. Yue G, Tang J, Zhang L, Niu H, Li H, Luo SJJoGO. CD276 suppresses CAR-T cell function by promoting tumor cell glycolysis in esophageal squamous cell carcinoma. J Gastrointest Oncol. 2021;12(1):38.
2. Melero I, Rouzaut A, Motz GT, Coukos GJCd. T-cell and NK-cell infiltration into solid tumors: a key limiting factor for efficacious cancer immunotherapy. Cancer Discov. 2014;4(5):522-6.
3. Labani-Motlagh A, Ashja-Mahdavi M, Loskog AJFiI. The tumor microenvironment: A milieu hindering and obstructing antitumor immune responses. Front Immunol. 2020;11:940.
4. Fallah-Mehrjardi K, Mirzaei HR, Masoumi E, Jafarzadeh L, Rostamian H, Khakpoor-Koosheh M, et al. Pharmacological targeting of immune checkpoint A2aR improves function of anti-CD19 CAR T cells in vitro. Immunol Lett. 2020;223(26):44-52.
5. Rostamian H, Fallah-Mehrjardi K, Khakpoor-Koosheh M, Pawelek JM, Hadjati J, Brown CE, et al. A metabolic switch to memory CAR T cells: Implications for cancer treatment. Cancer Lett. 2021;500(14):107-18.
6. Ward PS, Thompson CBJCc. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer cell. 2012;21(3):297-308.
7. Corbet C, Feron OJNRC. Tumour acidosis: from the passenger to the driver's seat. Nat Rev Cancer. 2017;17(10):577.
8. Pérez-Tomás R, Pérez-Guillén IJC. Lactate in the Tumor Microenvironment: An Essential Molecule in Cancer Progression and Treatment. Cancers (Basel). 2020;12(11):3244.
9. Balgi AD, Diering GH, Donohue E, Lam KK, Fonseca BD, Zimmerman C, et al. Regulation of mTORC1 signaling by pH. PloS one. 2011;6(6):e21549.
10. Romero-Garcia S, Moreno-Altamirano MMB, Prado-Garcia H, Sánchez-García FJJFii. Lactate contribution to the tumor microenvironment: mechanisms, effects on immune cells and therapeutic relevance. Front Immunol. 2016;7(2):52.
11. Ganapathy-Kanniappan S, Geschwind J-FHJMc. Tumor glycolysis as a target for cancer therapy: progress and prospects. Mol Cancer. 2013;12(1):1-11.
12. Clower CV, Chatterjee D, Wang Z, Cantley LC, Vander Heiden MG, Krainer ARJPotNAoS. The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proc Natl Acad Sci. 2010;107(5):1894-9.
13. Zahra K, Dey T, Mishra SP, Pandey UJFio. Pyruvate kinase M2 and cancer: the role of PKM2 in promoting tumorigenesis. Front Oncol. 2020;10:159.
14. Peng Y, Croce CMJSt, therapy t. The role of MicroRNAs in human cancer. Signal transduction and targeted therapy. 2016;1(1):1-9.
15. Jia X, Wang X, Guo X, Ji J, Lou G, Zhao J, et al. MicroRNA‐124: an emerging therapeutic target in cancer. Cancer Medicine. 2019;8(12):5638-50.
16. Sun Y, Zhao X, Zhou Y, Hu YJOr. miR-124, miR-137 and miR-340 regulate colorectal cancer growth via inhibition of the Warburg effect. Oncology reports. 2012;28(4):1346-52.
17. Taniguchi K, Sugito N, Kumazaki M, Shinohara H, Yamada N, Nakagawa Y, et al. MicroRNA-124 inhibits cancer cell growth through PTB1/PKM1/PKM2 feedback cascade in colorectal cancer. Cancer Lett. 2015;363(1):17-27.
18. Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundfør K, Rofstad EK, et al. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. 2000;60(4):916-21.
19. Walenta S, Salameh A, Lyng H, Evensen JF, Mitze M, Rofstad EK, et al. Correlation of high lactate levels in head and neck tumors with incidence of metastasis. 1997;150(2):409.
20. Brizel DM, Schroeder T, Scher RL, Walenta S, Clough RW, Dewhirst MW, et al. Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. 2001;51(2):349-53.
21. Yokota H, Guo J, Matoba M, Higashi K, Tonami H, Nagao YJJoMRIAOJotISfMRiM. Lactate, choline, and creatine levels measured by vitro 1H‐MRS as prognostic parameters in patients with non‐small‐cell lung cancer. 2007;25(5):992-9.
22. Qian J, Gong Z-c, Zhang Y-n, Wu H-h, Zhao J, Wang L-t, et al. Lactic acid promotes metastatic niche formation in bone metastasis of colorectal cancer. Cell Commun Signal. 2021;19(1):1-15.
23. Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 2016;24(5):657-71.
24. Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, et al. Inhibitory effect of tumor cell–derived lactic acid on human T cells. 2007;109(9):3812-9.
25. Pilon-Thomas S, Kodumudi KN, El-Kenawi AE, Russell S, Weber AM, Luddy K, et al. Neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer Res. 2016;76(6):1381-90.
26. Quinn III WJ, Jiao J, TeSlaa T, Stadanlick J, Wang Z, Wang L, et al. Lactate limits T cell proliferation via the NAD (H) redox state. Cell Rep. 2020;33(11):108500.
27. Lim AR, Rathmell WK, Rathmell JCJE. The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy. Elife. 2020;9:e55185.
28. Calcinotto A, Filipazzi P, Grioni M, Iero M, De Milito A, Ricupito A, et al. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res. 2012;72(11):2746-56.
29. Cascone T, McKenzie JA, Mbofung RM, Punt S, Wang Z, Xu C, et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab. 2018;27(5):977-87. e4.
30. Renner K, Bruss C, Schnell A, Koehl G, Becker HM, Fante M, et al. Restricting glycolysis preserves T cell effector functions and augments checkpoint therapy. Cell Rep. 2019;29(1):135-50. e9.
31. Luo W, Semenza GLJTiE, Metabolism. Emerging roles of PKM2 in cell metabolism and cancer progression. Trends in Endocrinology & Metabolism. 2012;23(11):560-6.
32. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. 2008;452(7184):230-3.
33. Qiu Z, Guo W, Wang Q, Chen Z, Huang S, Zhao F, et al. MicroRNA-124 reduces the pentose phosphate pathway and proliferation by targeting PRPS1 and RPIA mRNAs in human colorectal cancer cells. Gastroenterology. 2015;149(6):1587-98. e11.
34. Taniguchi K, Ito Y, Sugito N, Kumazaki M, Shinohara H, Yamada N, et al. Organ-specific PTB1-associated microRNAs determine expression of pyruvate kinase isoforms. Sci Rep. 2015;5(1):1-8.
35. Rundqvist H, Veliça P, Barbieri L, Gameiro P, Cunha PP, Gojkovic M, et al. Lactate potentiates differentiation and expansion of cytotoxic T cells. 2019.
36. Wen J, Cheng S, Zhang Y, Wang R, Xu J, Ling Z, et al. Lactate anions participate in T cell cytokine production and function. Sci China Life Sci. 2021:1-11.
37. Zhang Y, Wen J, Sun B. Lactate is critical for cytokines production of T cell after TCR activation. Am Assoc Immnol. 2020;204(1 Supplement):240.3.
38. Polanczyk MJ, Walker E, Haley D, Guerrouahen BS, Akporiaye ETJJotm. Blockade of TGF-β signaling to enhance the antitumor response is accompanied by dysregulation of the functional activity of CD4+ CD25+ Foxp3+ and CD4+ CD25− Foxp3+ T cells. J Transl Med. 2019;17(1):1-12.
39. Masoumi E, Jafarzadeh L, Mirzaei HR, Alishah K, Fallah-Mehrjardi K, Rostamian H, et al. Genetic and pharmacological targeting of A2a receptor improves function of anti-mesothelin CAR T cells. 2020;39(1):1-12.
40. Kanchan RK, Perumal N, Atri P, Chirravuri Venkata R, Thapa I, Klinkebiel DL, et al. MiR‐1253 exerts tumor‐suppressive effects in medulloblastoma via inhibition of CDK6 and CD276 (B7‐H3). Brain Pathol. 2020;30(4):732-45.
41. Yue G, Tang J, Zhang L, Niu H, Li H, Luo SJJoGO. CD276 suppresses CAR-T cell function by promoting tumor cell glycolysis in esophageal squamous cell carcinoma. J Gastrointest Oncol. 2021;12(1):38.
| Files | ||
| Issue | Vol 22 No 1 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v22i1.12007 | |
| Keywords | ||
| Lactic acid Metabolism MIRN124 microRNA, human T-lymphocytes Tumor microenvironment | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Khakpoor-Koosheh M, Rostamian H, Masoumi E, Jafarzadeh L, Fallah-Mehrjardi K, Javad Tavassolifar M, Noorbakhsh F, Mirzaei HR, Hadjati jamshid, Rezaei N. MicroRNA-124 Enhances T Cells Functions by Manipulating the Lactic Acid Metabolism of Tumor Cells. Iran J Allergy Asthma Immunol. 2023;22(1):62-71.
