CD8+ T-cells Co-expressing PD-1 and TIGIT Are Highly Frequent in Chronic Lymphocytic Leukemia
PD-1 and TIGIT Co-expression in CLL
-
Reza Hajiasghar-Sharbaf
,
Hossein Asgarian-Omran
,
Reza Valadan
,
Hadi Hossein-Nattaj
,
Ramin Shekarriz
,
Ehsan Zaboli
,
Ghasem Janbabaei
,
Mohsen Tehrani
Abstract
The role of immune checkpoint receptors in T-cell exhaustion has been demonstrated in several cancers. We investigated the co-expression of TIGIT/PD-1 and LAG-3/PD-1 cells in patients with chronic lymphocytic leukemia (CLL).
The frequencies of TIGIT+PD-1+CD8+and LAG-3+PD-1+CD8+cells and relative mRNA expression of LSECtin and CD155 were examined in PBMCs from 33 CLL patients and 20 controls.
The percentage of TIGIT+PD-1+CD8+cells was significantly higher in CLL patients than in control subjects, with the preference in advanced stage patients. However, LAG-3+PD-1+CD8+cell percentage was significantly lower in CLL patients than in the control subjects and no significant difference were found between the early and advanced stages of the disease. An increase in the mRNA expression level of LSECtin, but not that of CD155, was observed in CLL patients compared to the control subjects.
Collectively, a higher co-expression of PD-1 and TIGIT on CD8+ T-cells in CLL compared to control subjects suggests an important role of TIGIT in T-cell exhaustion in CLL patients especially those with advanced disease.
1. Kotaskova J, Tichy B, Trbusek M, Francova HS, Kabathova J, Malcikova J, et al. High expression of lymphocyte-activation gene 3 (LAG3) in chronic lymphocytic leukemia cells is associated with unmutated immunoglobulin variable heavy chain region (IGHV) gene and reduced treatment-free survival. J Mol Diagn. 2010;12(3):328-34.
2. Herishanu Y, Katz BZ, Lipsky A, Wiestner A. Biology of chronic lymphocytic leukemia in different microenvironments: clinical and therapeutic implications. Hematol Oncol Clin North Am. 2013;27(2):173-206.
3. Garcia-Escobar I, Sepulveda J, Castellano D, Cortes-Funes H. Therapeutic management of chronic lymphocytic leukaemia: state of the art and future perspectives. Crit Rev Oncol Hematol. 2011;80(1):100-13.
4. Nunes C, Wong R, Mason M, Fegan C, Man S, Pepper C. Expansion of a CD8(+)PD-1(+) replicative senescence phenotype in early stage CLL patients is associated with inverted CD4:CD8 ratios and disease progression. Clin Cancer Res. 2012;18(3):678-87.
5. Morrison VA. Infectious complications of chronic lymphocytic leukaemia: pathogenesis, spectrum of infection, preventive approaches. Best Pract Res Clin Haematol. 2010;23(1):145-53.
6. Riches JC, Davies JK, McClanahan F, Fatah R, Iqbal S, Agrawal S, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood. 2013;121(9):1612-21.
7. Jiang Y, Li Y, Zhu B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis. 2015;6:e1792.
8. Zhang Z, Liu S, Zhang B, Qiao L, Zhang Y, Zhang Y. T Cell Dysfunction and Exhaustion in Cancer. Front Cell Dev Biol. 2020;8:17.
9. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15(8):486-99.
10. Te Raa GD, Pascutti MF, Garcia-Vallejo JJ, Reinen E, Remmerswaal EB, ten Berge IJ, et al. CMV-specific CD8+ T-cell function is not impaired in chronic lymphocytic leukemia. Blood. 2014;123(5):717-24.
11. Palma M, Gentilcore G, Heimersson K, Mozaffari F, Nasman-Glaser B, Young E, et al. T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers. Haematologica. 2017;102(3):562-72.
12. Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10(1):29-37.
13. Jing W, Gershan JA, Weber J, Tlomak D, McOlash L, Sabatos-Peyton C, et al. Combined immune checkpoint protein blockade and low dose whole body irradiation as immunotherapy for myeloma. J Immunother Cancer. 2015;3(1):2.
14. Legat A, Speiser DE, Pircher H, Zehn D, Fuertes Marraco SA. Inhibitory Receptor Expression Depends More Dominantly on Differentiation and Activation than "Exhaustion" of Human CD8 T Cells. Front Immunol. 2013;4:455.
15. 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.
16. Gandhi MK, Lambley E, Duraiswamy J, Dua U, Smith C, Elliott S, et al. Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8+ T-cell function in Hodgkin lymphoma patients. Blood. 2006;108(7):2280-9.
17. Goding SR, Wilson KA, Xie Y, Harris KM, Baxi A, Akpinarli A, et al. Restoring immune function of tumor-specific CD4+ T cells during recurrence of melanoma. J Immunol. 2013;190(9):4899-909.
18. Xu F, Liu J, Liu D, Liu B, Wang M, Hu Z, et al. LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Res. 2014;74(13):3418-28.
19. Workman CJ, Wang Y, El Kasmi KC, Pardoll DM, Murray PJ, Drake CG, et al. LAG-3 regulates plasmacytoid dendritic cell homeostasis. J Immunol. 2009;182(4):1885-91.
20. Blake SJ, Dougall WC, Miles JJ, Teng MW, Smyth MJ. Molecular Pathways: Targeting CD96 and TIGIT for Cancer Immunotherapy. Clin Cancer Res. 2016;22(21):5183-8.
21. 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.
22. Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell. 2014;26(6):923-37.
23. Kong Y, Zhu L, Schell TD, Zhang J, Claxton DF, Ehmann WC, et al. T-Cell Immunoglobulin and ITIM Domain (TIGIT) Associates with CD8+ T-Cell Exhaustion and Poor Clinical Outcome in AML Patients. Clin Cancer Res. 2016;22(12):3057-66.
24. Inozume T, Yaguchi T, Furuta J, Harada K, Kawakami Y, Shimada S. Melanoma Cells Control Antimelanoma CTL Responses via Interaction between TIGIT and CD155 in the Effector Phase. J Invest Dermatol. 2016;136(1):255-63.
25. Taghiloo S, Allahmoradi E, Tehrani M, Hossein-Nataj H, Shekarriz R, Janbabaei G, et al. Frequency and functional characterization of exhausted CD8(+) T cells in chronic lymphocytic leukemia. Eur J Haematol. 2017;98(6):622-31.
26. Allahmoradi E, Taghiloo S, Tehrani M, Hossein-Nattaj H, Janbabaei G, Shekarriz R, et al. CD4+ T Cells are Exhausted and Show Functional Defects in Chronic Lymphocytic Leukemia. Iran J Immunol. 2017;14(4):257-69.
27. 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.
28. Catakovic K, Gassner FJ, Ratswohl C, Zaborsky N, Rebhandl S, Schubert M, et al. TIGIT expressing CD4+T cells represent a tumor-supportive T cell subset in chronic lymphocytic leukemia. Oncoimmunology. 2017;7(1):e1371399.
29. 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.
30. Grzywnowicz M, Zaleska J, Mertens D, Tomczak W, Wlasiuk P, Kosior K, et al. Programmed death-1 and its ligand are novel immunotolerant molecules expressed on leukemic B cells in chronic lymphocytic leukemia. PLoS One. 2012;7(4):e35178.
31. 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.
32. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46(2):219-234. Blood. 2016;128(17):2109.
33. 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.
34. Clarke JM, George DJ, Lisi S, Salama AKS. Immune Checkpoint Blockade: The New Frontier in Cancer Treatment. Target Oncol. 2018;13(1):1-20.
35. Hung AL, Maxwell R, Theodros D, Belcaid Z, Mathios D, Luksik AS, et al. TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM. Oncoimmunology. 2018;7(8):e1466769.
36. Wang M, Bu J, Zhou M, Sido J, Lin Y, Liu G, et al. CD8(+)T cells expressing both PD-1 and TIGIT but not CD226 are dysfunctional in acute myeloid leukemia (AML) patients. Clin Immunol. 2018;190:64-73.
37. Josefsson SE, Beiske K, Blaker YN, Forsund MS, Holte H, Ostenstad B, et al. TIGIT and PD-1 mark intratumoral T cells with reduced effector function in B-cell non-Hodgkin lymphoma. Cancer Immunol Res. 2019.
38. Nishiwada S, Sho M, Yasuda S, Shimada K, Yamato I, Akahori T, et al. Clinical significance of CD155 expression in human pancreatic cancer. Anticancer Res. 2015;35(4):2287-97.
39. Huang RY, Eppolito C, Lele S, Shrikant P, Matsuzaki J, Odunsi K. LAG3 and PD1 co-inhibitory molecules collaborate to limit CD8+ T cell signaling and dampen antitumor immunity in a murine ovarian cancer model. Oncotarget. 2015;6(29):27359-77.
40. Huang RY, Francois A, McGray AR, Miliotto A, Odunsi K. Compensatory upregulation of PD-1, LAG-3, and CTLA-4 limits the efficacy of single-agent checkpoint blockade in metastatic ovarian cancer. Oncoimmunology. 2017;6(1):e1249561.
41. Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72(4):917-27.
42. Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A. 2010;107(17):7875-80.
43. Gassner FJ, Zaborsky N, Catakovic K, Rebhandl S, Huemer M, Egle A, et al. Chronic lymphocytic leukaemia induces an exhausted T cell phenotype in the TCL1 transgenic mouse model. Br J Haematol. 2015;170(4):515-22.
44. Shapiro M, Herishanu Y, Katz BZ, Dezorella N, Sun C, Kay S, et al. Lymphocyte activation gene 3: a novel therapeutic target in chronic lymphocytic leukemia. Haematologica. 2017;102(5):874-82.
2. Herishanu Y, Katz BZ, Lipsky A, Wiestner A. Biology of chronic lymphocytic leukemia in different microenvironments: clinical and therapeutic implications. Hematol Oncol Clin North Am. 2013;27(2):173-206.
3. Garcia-Escobar I, Sepulveda J, Castellano D, Cortes-Funes H. Therapeutic management of chronic lymphocytic leukaemia: state of the art and future perspectives. Crit Rev Oncol Hematol. 2011;80(1):100-13.
4. Nunes C, Wong R, Mason M, Fegan C, Man S, Pepper C. Expansion of a CD8(+)PD-1(+) replicative senescence phenotype in early stage CLL patients is associated with inverted CD4:CD8 ratios and disease progression. Clin Cancer Res. 2012;18(3):678-87.
5. Morrison VA. Infectious complications of chronic lymphocytic leukaemia: pathogenesis, spectrum of infection, preventive approaches. Best Pract Res Clin Haematol. 2010;23(1):145-53.
6. Riches JC, Davies JK, McClanahan F, Fatah R, Iqbal S, Agrawal S, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood. 2013;121(9):1612-21.
7. Jiang Y, Li Y, Zhu B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis. 2015;6:e1792.
8. Zhang Z, Liu S, Zhang B, Qiao L, Zhang Y, Zhang Y. T Cell Dysfunction and Exhaustion in Cancer. Front Cell Dev Biol. 2020;8:17.
9. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15(8):486-99.
10. Te Raa GD, Pascutti MF, Garcia-Vallejo JJ, Reinen E, Remmerswaal EB, ten Berge IJ, et al. CMV-specific CD8+ T-cell function is not impaired in chronic lymphocytic leukemia. Blood. 2014;123(5):717-24.
11. Palma M, Gentilcore G, Heimersson K, Mozaffari F, Nasman-Glaser B, Young E, et al. T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers. Haematologica. 2017;102(3):562-72.
12. Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10(1):29-37.
13. Jing W, Gershan JA, Weber J, Tlomak D, McOlash L, Sabatos-Peyton C, et al. Combined immune checkpoint protein blockade and low dose whole body irradiation as immunotherapy for myeloma. J Immunother Cancer. 2015;3(1):2.
14. Legat A, Speiser DE, Pircher H, Zehn D, Fuertes Marraco SA. Inhibitory Receptor Expression Depends More Dominantly on Differentiation and Activation than "Exhaustion" of Human CD8 T Cells. Front Immunol. 2013;4:455.
15. 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.
16. Gandhi MK, Lambley E, Duraiswamy J, Dua U, Smith C, Elliott S, et al. Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8+ T-cell function in Hodgkin lymphoma patients. Blood. 2006;108(7):2280-9.
17. Goding SR, Wilson KA, Xie Y, Harris KM, Baxi A, Akpinarli A, et al. Restoring immune function of tumor-specific CD4+ T cells during recurrence of melanoma. J Immunol. 2013;190(9):4899-909.
18. Xu F, Liu J, Liu D, Liu B, Wang M, Hu Z, et al. LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Res. 2014;74(13):3418-28.
19. Workman CJ, Wang Y, El Kasmi KC, Pardoll DM, Murray PJ, Drake CG, et al. LAG-3 regulates plasmacytoid dendritic cell homeostasis. J Immunol. 2009;182(4):1885-91.
20. Blake SJ, Dougall WC, Miles JJ, Teng MW, Smyth MJ. Molecular Pathways: Targeting CD96 and TIGIT for Cancer Immunotherapy. Clin Cancer Res. 2016;22(21):5183-8.
21. 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.
22. Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell. 2014;26(6):923-37.
23. Kong Y, Zhu L, Schell TD, Zhang J, Claxton DF, Ehmann WC, et al. T-Cell Immunoglobulin and ITIM Domain (TIGIT) Associates with CD8+ T-Cell Exhaustion and Poor Clinical Outcome in AML Patients. Clin Cancer Res. 2016;22(12):3057-66.
24. Inozume T, Yaguchi T, Furuta J, Harada K, Kawakami Y, Shimada S. Melanoma Cells Control Antimelanoma CTL Responses via Interaction between TIGIT and CD155 in the Effector Phase. J Invest Dermatol. 2016;136(1):255-63.
25. Taghiloo S, Allahmoradi E, Tehrani M, Hossein-Nataj H, Shekarriz R, Janbabaei G, et al. Frequency and functional characterization of exhausted CD8(+) T cells in chronic lymphocytic leukemia. Eur J Haematol. 2017;98(6):622-31.
26. Allahmoradi E, Taghiloo S, Tehrani M, Hossein-Nattaj H, Janbabaei G, Shekarriz R, et al. CD4+ T Cells are Exhausted and Show Functional Defects in Chronic Lymphocytic Leukemia. Iran J Immunol. 2017;14(4):257-69.
27. 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.
28. Catakovic K, Gassner FJ, Ratswohl C, Zaborsky N, Rebhandl S, Schubert M, et al. TIGIT expressing CD4+T cells represent a tumor-supportive T cell subset in chronic lymphocytic leukemia. Oncoimmunology. 2017;7(1):e1371399.
29. 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.
30. Grzywnowicz M, Zaleska J, Mertens D, Tomczak W, Wlasiuk P, Kosior K, et al. Programmed death-1 and its ligand are novel immunotolerant molecules expressed on leukemic B cells in chronic lymphocytic leukemia. PLoS One. 2012;7(4):e35178.
31. 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.
32. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46(2):219-234. Blood. 2016;128(17):2109.
33. 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.
34. Clarke JM, George DJ, Lisi S, Salama AKS. Immune Checkpoint Blockade: The New Frontier in Cancer Treatment. Target Oncol. 2018;13(1):1-20.
35. Hung AL, Maxwell R, Theodros D, Belcaid Z, Mathios D, Luksik AS, et al. TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM. Oncoimmunology. 2018;7(8):e1466769.
36. Wang M, Bu J, Zhou M, Sido J, Lin Y, Liu G, et al. CD8(+)T cells expressing both PD-1 and TIGIT but not CD226 are dysfunctional in acute myeloid leukemia (AML) patients. Clin Immunol. 2018;190:64-73.
37. Josefsson SE, Beiske K, Blaker YN, Forsund MS, Holte H, Ostenstad B, et al. TIGIT and PD-1 mark intratumoral T cells with reduced effector function in B-cell non-Hodgkin lymphoma. Cancer Immunol Res. 2019.
38. Nishiwada S, Sho M, Yasuda S, Shimada K, Yamato I, Akahori T, et al. Clinical significance of CD155 expression in human pancreatic cancer. Anticancer Res. 2015;35(4):2287-97.
39. Huang RY, Eppolito C, Lele S, Shrikant P, Matsuzaki J, Odunsi K. LAG3 and PD1 co-inhibitory molecules collaborate to limit CD8+ T cell signaling and dampen antitumor immunity in a murine ovarian cancer model. Oncotarget. 2015;6(29):27359-77.
40. Huang RY, Francois A, McGray AR, Miliotto A, Odunsi K. Compensatory upregulation of PD-1, LAG-3, and CTLA-4 limits the efficacy of single-agent checkpoint blockade in metastatic ovarian cancer. Oncoimmunology. 2017;6(1):e1249561.
41. Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72(4):917-27.
42. Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A. 2010;107(17):7875-80.
43. Gassner FJ, Zaborsky N, Catakovic K, Rebhandl S, Huemer M, Egle A, et al. Chronic lymphocytic leukaemia induces an exhausted T cell phenotype in the TCL1 transgenic mouse model. Br J Haematol. 2015;170(4):515-22.
44. Shapiro M, Herishanu Y, Katz BZ, Dezorella N, Sun C, Kay S, et al. Lymphocyte activation gene 3: a novel therapeutic target in chronic lymphocytic leukemia. Haematologica. 2017;102(5):874-82.
| Files | ||
| Issue | Vol 20 No 6 (2021) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v20i6.8027 | |
| Keywords | ||
| Chronic lymphocytic leukemia TIGIT protein | ||
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How to Cite
1.
Hajiasghar-Sharbaf R, Asgarian-Omran H, Valadan R, Hossein-Nattaj H, Shekarriz R, Zaboli E, Janbabaei G, Tehrani M. CD8+ T-cells Co-expressing PD-1 and TIGIT Are Highly Frequent in Chronic Lymphocytic Leukemia. Iran J Allergy Asthma Immunol. 2021;20(6):751-763.
