CD8+ T Cells in Acute Lymphoblastic Leukemia Show a Progenitor-exhausted Phenotype
-
Armin Akbar
,
Hossein Asgarian-Omran
,
Reza Valadan
,
Ahmad Najafi
,
Ramin Shekarriz
,
Ehsan Zaboli
,
Mohammad Eslami-Jouybari
,
Hossein Karami
,
Mohammad Naderisoraki
,
Mohsen Tehrani
Abstract
Exhausted T cells are phenotypically and functionally heterogeneous, from progenitor- to terminally-exhausted T cells. We evaluated gene expression profile of CD8+ T cells in acute leukemia to characterize the phenotype of exhausted T cells.
Blood samples were collected from acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) patients prior to treatment and from control subjects. Additionally, samples were obtained from ALL patients after induction therapy. TCF7, NFATc1, IRF4, and BATF gene expression was then evaluated in isolated CD8+ T cells.
CD8+ T cells from ALL patients showed higher expression of TCF7 and NFATc1 compared to the control group. The two study groups did not have a significant difference in the expression of BATF and IRF4. When compared to the control group, CD8+ T cells of AML patients showed an elevated expression level of NAFTc1 and IRF4. Significant differences were not found between the two study groups in AML when it came to the expression of BATF and TCF7.
To our findings, the majority of CD8+ T cells found in ALL patients consist of progenitor-exhausted T cells.
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2. Juliusson G, Hough R. Leukemia. Prog Tumor Res. 2016;43:87-100.
3. Devine SM, Larson RA. Acute leukemia in adults: recent developments in diagnosis and treatment. CA Cancer J Clin. 1994;44(6):326-52.
4. Kiem Hao T, Nhu Hiep P, Kim Hoa NT, Van Ha C. Causes of Death in Childhood Acute Lymphoblastic Leukemia at Hue Central Hospital for 10 Years (2008-2018). Glob Pediatr Health. 2020;7:2333794x20901930.
5. Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997-2002. Cancer causes control : CCC. 2008;19(4):379-90.
6. De Kouchkovsky I, Abdul-Hay M. 'Acute myeloid leukemia: a comprehensive review and 2016 update'. Blood Cancer J. 2016;6(7):e441.
7. García-Escobar I, Sepúlveda J, Castellano D, Cortés-Funes H. Therapeutic management of chronic lymphocytic leukaemia: state of the art and future perspectives. Critical Rev Oncol. 2011;80(1):100-13.
8. Shi N, Luo Y, Xu Y, Liang J, Ma A, Gan Y, et al. DAP10 Predicted the Outcome of Pediatric B-Cell Acute Lymphoblastic Leukemia and Was Associated with the T-Cell Exhaustion. Journal of oncology. 2021;2021:4824868.
9. Hao F, Sholy C, Wang C, Cao M, Kang X. The Role of T Cell Immunotherapy in Acute Myeloid Leukemia. Cells. 2021;10(12).
10. Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity. 2016;44(5):989-1004.
11. Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12(6):492-9.
12. Hatefi F, Asgarian-Omran H, Hossein-Nataj H, Akbar A, Shekarriz R, Zaboli E, et al. Combined Blockade Of PD-1 and TIGIT is not Sufficient to Improve the Function Of CD8+ T-Cells in Chronic Lymphocytic Leukemia. Asian Pac J Cancer Prev. 2022;23(7):2225-31.
13. Rezazadeh H, Astaneh M, Tehrani M, Hossein-Nataj H, Zaboli E, Shekarriz R, et al. Blockade of PD-1 and TIM-3 immune checkpoints fails to restore the function of exhausted CD8(+) T cells in early clinical stages of chronic lymphocytic leukemia. Immunol Res. 2020;68(5):269-79.
14. Kallies A, Zehn D, Utzschneider DT. Precursor exhausted T cells: key to successful immunotherapy? Nat Rev Immunol. 2020;20(2):128-36.
15. Pan MG, Xiong Y, Chen F. NFAT gene family in inflammation and cancer. Curr Mol Med. 2013;13(4):543-54.
16. Oestreich KJ, Yoon H, Ahmed R, Boss JM. NFATc1 regulates PD-1 expression upon T cell activation. J immunol. 2008;181(7):4832-9.
17. Vaeth M, Eckstein M, Shaw PJ, Kozhaya L, Yang J, Berberich-Siebelt F, et al. Store-operated Ca2+ entry in follicular T cells controls humoral immune responses and autoimmunity. Immunity. 2016;44(6):1350-64.
18. Man K, Gabriel SS, Liao Y, Gloury R, Preston S, Henstridge DC, et al. Transcription Factor IRF4 Promotes CD8(+) T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection. Immunity. 2017;47(6):1129-41.e5.
19. Quigley M, Pereyra F, Nilsson B, Porichis F, Fonseca C, Eichbaum Q, et al. Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat Med. 2010;16(10):1147-51.
20. Kurachi M, Barnitz RA, Yosef N, Odorizzi PM, DiIorio MA, Lemieux ME, et al. The transcription factor BATF operates as an essential differentiation checkpoint in early effector CD8+ T cells. Nat Immunol. 2014;15(4):373-83.
21. Klein-Hessling S, Muhammad K, Klein M, Pusch T, Rudolf R, Flöter J, et al. NFATc1 controls the cytotoxicity of CD8(+) T cells. Nat Commun. 2017;8(1):511.
22. Siddiqui I, Schaeuble K, Chennupati V, Fuertes Marraco SA, Calderon-Copete S, Pais Ferreira D, et al. Intratumoral Tcf1(+)PD-1(+)CD8(+) T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy. Immunity. 2019;50(1):195-211.e10.
23. Gounari F, Khazaie K. TCF-1: a maverick in T cell development and function. Nat Immunol. 2022;23(5):671-8.
24. Chauvin JM, Pagliano O, Fourcade J, Sun Z, Wang H, Sander C, et al. TIGIT and PD-1 impair tumor antigen-specific CD8⁺ T cells in melanoma patients. J Clin Invest. 2015;125(5):2046-58.
25. Gros A, Robbins PF, Yao X, Li YF, Turcotte S, Tran E, et al. PD-1 identifies the patient-specific CD8⁺ tumor-reactive repertoire infiltrating human tumors. J Clin Invest. 2014;124(5):2246-59.
26. Toor SM, Murshed K, Al-Dhaheri M, Khawar M, Abu Nada M, Elkord E. Immune Checkpoints in Circulating and Tumor-Infiltrating CD4(+) T Cell Subsets in Colorectal Cancer Patients. Front Immunol. 2019;10:2936.
27. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-90.
28. Kurachi M. CD8+ T cell exhaustion. Seminars Immunopathol. 2019;41(3):327-37.
29. Shen Z, Gu X, Cao H, Mao W, Yang L, He M, et al. Characterization of microbiota in acute leukemia patients following successful remission induction chemotherapy without antimicrobial prophylaxis. Int Microbiol. 2021;24(2):263-73.
30. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402-8.
31. Seo W, Jerin C, Nishikawa H. Transcriptional regulatory network for the establishment of CD8(+) T cell exhaustion. Exp Mol Med. 2021;53(2):202-9.
32. Zhang J, Lyu T, Cao Y, Feng H. Role of TCF-1 in differentiation, exhaustion, and memory of CD8(+) T cells: A review. Faseb j. 2021;35(5):e21549.
33. Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP, et al. TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion. Nature. 2019;571(7764):211-8.
34. Yao C, Sun HW, Lacey NE, Ji Y, Moseman EA, Shih HY, et al. Single-cell RNA-seq reveals TOX as a key regulator of CD8(+) T cell persistence in chronic infection. Nat Immunol. 2019;20(7):890-901.
35. Miller BC, Sen DR, Al Abosy R, Bi K, Virkud YV, LaFleur MW, et al. Subsets of exhausted CD8(+) T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol. 2019;20(3):326-36.
36. Mohammadi M, Asgarian-Omran H, Najafi B, Najafi A, Valadan R, Karami H, et al. Evaluation of mRNA Expressions of TOX and NR4As in CD8+ T cells in Acute Leukemia. Iran J Immunol. 2023;20(4):438-45.
37. Shahbaz S, Dunsmore G, Koleva P, Xu L, Houston S, Elahi S. Galectin-9 and VISTA Expression Define Terminally Exhausted T Cells in HIV-1 Infection. J Immunol. 2020;204(9):2474-91.
38. Akbar A, Asgarian-Omran H, Valadan R, Dindarloo MM, Najafi A, Kahrizi A, et al. Expression of Galectin-9-related immune checkpoint receptors in B-cell acute lymphoblastic leukemia. Iran J Basic Med Sci. 2023;26(12):1468-74.
39. Koller P, Baran N, Harutyunyan K, Cavazos A, Mallampati S, Chin RL, et al. PD-1 blockade in combination with dasatinib potentiates induction of anti-acute lymphocytic leukemia immunity. J Immunother Cancer. 2023;11(10).
40. Zeidner JF, Vincent BG, Ivanova A, Moore D, McKinnon KP, Wilkinson AD, et al. Phase II Trial of Pembrolizumab after High-Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia. Blood Cancer Discov. 2021;2(6):616-29.
41. Brauneck F, Haag F, Woost R, Wildner N, Tolosa E, Rissiek A, et al. Increased frequency of TIGIT(+)CD73-CD8(+) T cells with a TOX(+) TCF-1low profile in patients with newly diagnosed and relapsed AML. Oncoimmunology. 2021;10(1):1930391.
2. Juliusson G, Hough R. Leukemia. Prog Tumor Res. 2016;43:87-100.
3. Devine SM, Larson RA. Acute leukemia in adults: recent developments in diagnosis and treatment. CA Cancer J Clin. 1994;44(6):326-52.
4. Kiem Hao T, Nhu Hiep P, Kim Hoa NT, Van Ha C. Causes of Death in Childhood Acute Lymphoblastic Leukemia at Hue Central Hospital for 10 Years (2008-2018). Glob Pediatr Health. 2020;7:2333794x20901930.
5. Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997-2002. Cancer causes control : CCC. 2008;19(4):379-90.
6. De Kouchkovsky I, Abdul-Hay M. 'Acute myeloid leukemia: a comprehensive review and 2016 update'. Blood Cancer J. 2016;6(7):e441.
7. García-Escobar I, Sepúlveda J, Castellano D, Cortés-Funes H. Therapeutic management of chronic lymphocytic leukaemia: state of the art and future perspectives. Critical Rev Oncol. 2011;80(1):100-13.
8. Shi N, Luo Y, Xu Y, Liang J, Ma A, Gan Y, et al. DAP10 Predicted the Outcome of Pediatric B-Cell Acute Lymphoblastic Leukemia and Was Associated with the T-Cell Exhaustion. Journal of oncology. 2021;2021:4824868.
9. Hao F, Sholy C, Wang C, Cao M, Kang X. The Role of T Cell Immunotherapy in Acute Myeloid Leukemia. Cells. 2021;10(12).
10. Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity. 2016;44(5):989-1004.
11. Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12(6):492-9.
12. Hatefi F, Asgarian-Omran H, Hossein-Nataj H, Akbar A, Shekarriz R, Zaboli E, et al. Combined Blockade Of PD-1 and TIGIT is not Sufficient to Improve the Function Of CD8+ T-Cells in Chronic Lymphocytic Leukemia. Asian Pac J Cancer Prev. 2022;23(7):2225-31.
13. Rezazadeh H, Astaneh M, Tehrani M, Hossein-Nataj H, Zaboli E, Shekarriz R, et al. Blockade of PD-1 and TIM-3 immune checkpoints fails to restore the function of exhausted CD8(+) T cells in early clinical stages of chronic lymphocytic leukemia. Immunol Res. 2020;68(5):269-79.
14. Kallies A, Zehn D, Utzschneider DT. Precursor exhausted T cells: key to successful immunotherapy? Nat Rev Immunol. 2020;20(2):128-36.
15. Pan MG, Xiong Y, Chen F. NFAT gene family in inflammation and cancer. Curr Mol Med. 2013;13(4):543-54.
16. Oestreich KJ, Yoon H, Ahmed R, Boss JM. NFATc1 regulates PD-1 expression upon T cell activation. J immunol. 2008;181(7):4832-9.
17. Vaeth M, Eckstein M, Shaw PJ, Kozhaya L, Yang J, Berberich-Siebelt F, et al. Store-operated Ca2+ entry in follicular T cells controls humoral immune responses and autoimmunity. Immunity. 2016;44(6):1350-64.
18. Man K, Gabriel SS, Liao Y, Gloury R, Preston S, Henstridge DC, et al. Transcription Factor IRF4 Promotes CD8(+) T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection. Immunity. 2017;47(6):1129-41.e5.
19. Quigley M, Pereyra F, Nilsson B, Porichis F, Fonseca C, Eichbaum Q, et al. Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat Med. 2010;16(10):1147-51.
20. Kurachi M, Barnitz RA, Yosef N, Odorizzi PM, DiIorio MA, Lemieux ME, et al. The transcription factor BATF operates as an essential differentiation checkpoint in early effector CD8+ T cells. Nat Immunol. 2014;15(4):373-83.
21. Klein-Hessling S, Muhammad K, Klein M, Pusch T, Rudolf R, Flöter J, et al. NFATc1 controls the cytotoxicity of CD8(+) T cells. Nat Commun. 2017;8(1):511.
22. Siddiqui I, Schaeuble K, Chennupati V, Fuertes Marraco SA, Calderon-Copete S, Pais Ferreira D, et al. Intratumoral Tcf1(+)PD-1(+)CD8(+) T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy. Immunity. 2019;50(1):195-211.e10.
23. Gounari F, Khazaie K. TCF-1: a maverick in T cell development and function. Nat Immunol. 2022;23(5):671-8.
24. Chauvin JM, Pagliano O, Fourcade J, Sun Z, Wang H, Sander C, et al. TIGIT and PD-1 impair tumor antigen-specific CD8⁺ T cells in melanoma patients. J Clin Invest. 2015;125(5):2046-58.
25. Gros A, Robbins PF, Yao X, Li YF, Turcotte S, Tran E, et al. PD-1 identifies the patient-specific CD8⁺ tumor-reactive repertoire infiltrating human tumors. J Clin Invest. 2014;124(5):2246-59.
26. Toor SM, Murshed K, Al-Dhaheri M, Khawar M, Abu Nada M, Elkord E. Immune Checkpoints in Circulating and Tumor-Infiltrating CD4(+) T Cell Subsets in Colorectal Cancer Patients. Front Immunol. 2019;10:2936.
27. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-90.
28. Kurachi M. CD8+ T cell exhaustion. Seminars Immunopathol. 2019;41(3):327-37.
29. Shen Z, Gu X, Cao H, Mao W, Yang L, He M, et al. Characterization of microbiota in acute leukemia patients following successful remission induction chemotherapy without antimicrobial prophylaxis. Int Microbiol. 2021;24(2):263-73.
30. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402-8.
31. Seo W, Jerin C, Nishikawa H. Transcriptional regulatory network for the establishment of CD8(+) T cell exhaustion. Exp Mol Med. 2021;53(2):202-9.
32. Zhang J, Lyu T, Cao Y, Feng H. Role of TCF-1 in differentiation, exhaustion, and memory of CD8(+) T cells: A review. Faseb j. 2021;35(5):e21549.
33. Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP, et al. TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion. Nature. 2019;571(7764):211-8.
34. Yao C, Sun HW, Lacey NE, Ji Y, Moseman EA, Shih HY, et al. Single-cell RNA-seq reveals TOX as a key regulator of CD8(+) T cell persistence in chronic infection. Nat Immunol. 2019;20(7):890-901.
35. Miller BC, Sen DR, Al Abosy R, Bi K, Virkud YV, LaFleur MW, et al. Subsets of exhausted CD8(+) T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol. 2019;20(3):326-36.
36. Mohammadi M, Asgarian-Omran H, Najafi B, Najafi A, Valadan R, Karami H, et al. Evaluation of mRNA Expressions of TOX and NR4As in CD8+ T cells in Acute Leukemia. Iran J Immunol. 2023;20(4):438-45.
37. Shahbaz S, Dunsmore G, Koleva P, Xu L, Houston S, Elahi S. Galectin-9 and VISTA Expression Define Terminally Exhausted T Cells in HIV-1 Infection. J Immunol. 2020;204(9):2474-91.
38. Akbar A, Asgarian-Omran H, Valadan R, Dindarloo MM, Najafi A, Kahrizi A, et al. Expression of Galectin-9-related immune checkpoint receptors in B-cell acute lymphoblastic leukemia. Iran J Basic Med Sci. 2023;26(12):1468-74.
39. Koller P, Baran N, Harutyunyan K, Cavazos A, Mallampati S, Chin RL, et al. PD-1 blockade in combination with dasatinib potentiates induction of anti-acute lymphocytic leukemia immunity. J Immunother Cancer. 2023;11(10).
40. Zeidner JF, Vincent BG, Ivanova A, Moore D, McKinnon KP, Wilkinson AD, et al. Phase II Trial of Pembrolizumab after High-Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia. Blood Cancer Discov. 2021;2(6):616-29.
41. Brauneck F, Haag F, Woost R, Wildner N, Tolosa E, Rissiek A, et al. Increased frequency of TIGIT(+)CD73-CD8(+) T cells with a TOX(+) TCF-1low profile in patients with newly diagnosed and relapsed AML. Oncoimmunology. 2021;10(1):1930391.
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How to Cite
1.
Akbar A, Asgarian-Omran H, Valadan R, Najafi A, Shekarriz R, Zaboli E, Eslami-Jouybari M, Karami H, Naderisoraki M, Tehrani M. CD8+ T Cells in Acute Lymphoblastic Leukemia Show a Progenitor-exhausted Phenotype. Iran J Allergy Asthma Immunol. 2026;:1-11.
