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Expression of PD-1 and TIM-3 inhibitory checkpoint molecules by T-lymphocytes in early post-transplant period in multiple myeloma patients

https://doi.org/10.35754/0234-5730-2021-66-4-499-511

Abstract

Introduction. High-dose chemotherapy (HDC) with autologous hematopoietic stem cell transplantation (auto-HSCT) is the standard of treatment for multiple myeloma (MM) patients. The post-transplant period appears to be promising for targeted anti-checkpoint therapy in MM.

Aim — to study the dynamics and functional properties of T-cells expressing inhibitory checkpoint molecules PD-1 and TIM-3 in patients with MM under conditions of lymphopenia after HDC with auto-HSCT.

Methods. The study included 40 patients with MM who underwent HDC with auto-HSCT. The counts of PD-1- and TIM3-positive CD8+ and CD4+ T-cells and their functional activity on the intracellular expression of Ki-67, production of granzyme B, and interferon-γ were assessed by fl ow cytometry.

Results. Relative counts of patient PD-1+ and TIM-3+ subsets of CD8+ and CD4+ T-cells obtained from bone marrow samples were higher compared to peripheral blood. CD8+ PD-1+ and CD4+ PD-1+ T-cells of MM patients had a pronounced cytotoxic and cytokine-producing potential. The functional activity of CD8+ TIM-3+ and CD4+ TIM-3+ T-cells was signifi cantly reduced compared with TIM-3-negative subsets. Low functional activity was also detected in populations of CD8+ and CD4+ T-lympho cytes, co-expressing PD-1 and TIM-3. The frequencies of T-cells expressing PD-1 and TIM-3 increased signifi cantly on the engraftment day after auto-HSCT. The proliferative activity of PD-1+ and TIM-3+ CD4+ and CD8+ T-cells and the cytotoxic potential of PD-1+ and TIM-3+ CD8+ T-cells were also signifi cantly increased compared to the data prior auto-HSCT.

Conclusions. PD-1-positive T-cells in MM patients are related to activated or “early dysfunctional” but not exhausted subsets, while T-cells exhaustion is more analogous with CD8+ TIM-3+ and CD4+ TIM-3+ T-cells, as well as with subsets co-expressing PD-1 and TIM-3. To identify the state of T-cells exhaustion, it is necessary to evaluate T-cells subsets co-expressing PD-1, TIM-3, and other ICMs, and/or to study their functional properties. In the early post-transplant period, the proportion of Tcells expressing PD-1 and TIM-3 increases due to an increase in their proliferative potential.

About the Authors

E. V. Batorov
Research Institute of Fundamental and Clinical Immunology
Russian Federation

Egor V. Batorov, Cand. Sci. (Med.), Senior Researcher, Laboratory of Cellular Immunotherapy

630099, Novosibirsk



V. V. Sergeevicheva
Research Institute of Fundamental and Clinical Immunology
Russian Federation

Vera V. Sergeevicheva, Cand. Sci. (Med.), Head of the Department of Haematology with Bone Marrow Transplantation Unit 

630099, Novosibirsk



T. A. Aristova
Research Institute of Fundamental and Clinical Immunology
Russian Federation

Tatiana A. Aristova, Physician, Department of Haematology with Bone Marrow Transplantation Unit 

630099, Novosibirsk



S. A. Sizikova
Research Institute of Fundamental and Clinical Immunology
Russian Federation

Svetlana A. Sizikova, Cand. Sci. (Med.), Physician, Department of Haematology with Bone Marrow Transplantation Unit 

630099, Novosibirsk



G. Y. Ushakova
Research Institute of Fundamental and Clinical Immunology
Russian Federation

Galina Yu. Ushakova, Cand. Sci. (Med.), Physician, Department of Haematology with Bone Marrow Transplantation Unit 

630099, Novosibirsk



A. V. Gilevich
Research Institute of Fundamental and Clinical Immunology
Russian Federation

Andrey V. Gilevich, Cand. Sci. (Med.), Head of the Intensive Care Unit 

630099, Novosibirsk



E. A. Shevela
Research Institute of Fundamental and Clinical Immunology
Russian Federation

Ekaterina Ya. Shevela, Dr. Sci. (Med.), Leading Researcher, Laboratory of Cellular Immunotherapy 

630099, Novosibirsk



A. A. Ostanin
Research Institute of Fundamental and Clinical Immunology
Russian Federation

Alexander A. Ostanin, Dr. Sci. (Med.), Professor, Chief Researcher, Laboratory of Cellular Immunotherapy 

630099, Novosibirsk



E. R. Chernykh
Research Institute of Fundamental and Clinical Immunology
Russian Federation

Elena R. Chernykh, Dr. Sci. (Med.), Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Laboratory of Cellular Immunotherapy 

630099, Novosibirsk



References

1. Kazandjian D. Multiple myeloma epidemiology and survival: A unique malignancy. Semin Oncol. 2016; 43(6): 676–81. DOI: 10.1053/j.seminoncol.2016.11.004.

2. Kumar S.K., Rajkumar S.V., Dispenzieri A., et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008; 111(5): 2516–20. DOI: 10.1182/blood-2007-10-116129.

3. Wherry E.J., Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015; 15(8): 486–99. DOI: 10.1038/nri3862.

4. Sabins N.C., Harman B.C., Barone L.R., et al. Differential expression of immune checkpoint modulators on in vitro primed CD4+ and CD8+ T cells. Front Immunol. 2016; 7: 221. DOI: 10.3389/fi mmu.2016.00221.

5. Schnorfeil F.M., Lichtenegger F.S., Emmerig K., et al. T cells are functionally not impaired in AML: Increased PD-1 expression is only seen at time of relapse and correlates with a shift towards the memory T cell compartment. J Hematol Oncol. 2015; 8: 93. DOI: 10.1186/s13045-015-0189-2.

6. Zelle-Rieser C., Thangavadivel S., Biedermann R., et al. T cells in multiple myeloma display features of exhaustion and senescence at the tumor site. J Hematol Oncol. 2016; 9(1): 116. DOI: 10.1186/s13045-016-0345-3.

7. Pianko M.J., Liu Y., Bagchi S., Lesokhin A.M. Immune checkpoint blockade for hematologic malignancies: A review. Stem Cell Investig. 2017; 4: 32. DOI: 10.21037/sci.2017.03.04.

8. Görgün G., Samur M.K., Cowens K.B., et al. Lenalidomide enhances immune checkpoint blockade-induced immune response in multiple myeloma. Clin Cancer Res. 2015; 21(20): 4607–18. DOI: 10.1158/1078-0432.CCR-15-0200.

9. Armand P., Engert A., Younes A., et al. Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: Extended follow-up of the multicohort single-arm phase II CheckMate 205 trial. J Clin Oncol. 2018; 36(14): 1428–39. DOI: 10.1200/JCO.2017.76.0793.

10. Chen R., Zinzani P.L., Fanale M.A., et al. Phase II study of the effi cacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol. 2017; 35(19): 2125–32. DOI: 10.1200/JCO.2016.72.1316.

11. Lesokhin A.M., Ansell S.M., Armand P., et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: Preliminary results of a phase Ib study. J Clin Oncol. 2016; 34(23): 2698–704. DOI: 10.1200/JCO.2015.65.9789.

12. Paiva B., Azpilikueta A., Puig N., et al. PD-L1/PD-1 presence in the tumor microenvironment and activity of PD-1 blockade in multiple myeloma. Leukemia. 2015; 29(10): 2110–3. DOI: 10.1038/leu.2015.79.

13. Benson D.M. Jr. Checkpoint inhibition in myeloma. Hematology Am Soc Hematol Educ Program. 2016; 2016(1): 528–33. DOI: 10.1182/asheducation-2016.1.528.

14. Marshall N., Hutchinson K., Marron T.U., et al. Antitumor T-cell homeostatic activation is uncoupled from homeostatic inhibition by checkpoint blockade. Cancer Discov. 2019; 9(11): 1520–37. DOI: 10.1158/2159-8290.CD-19-0391.

15. Minnie S.A., Kuns R.D., Gartlan K.H., et al. Myeloma escape after stem cell transplantation is a consequence of T-cell exhaustion and is prevented by TIGIT blockade. Blood. 2018; 132(16): 1675–88. DOI: 10.1182/blood-2018-01-825240.

16. Simonetta F., Pradier A., Bosshard C., et al. Dynamics of expression of programmed cell death protein-1 (PD-1) on T cells after allogeneic hematopoietic stem cell transplantation. Front Immunol. 2019; 10:1034. DOI: 10.3389/fi mmu.2019.01034.

17. Arruda L.C.M., Lima-Júnior J.R., Clave E., et al. Homeostatic proliferation leads to telomere attrition and increased PD-1 expression after autologous hematopoietic SCT for systemic sclerosis. Bone Marrow Transplant. 2018; 53(10): 1319–27. DOI: 10.1038/s41409-018-0162-0.

18. Chung D.J., Pronschinske K.B., Shyer J.A., et al. T-cell exhaustion in multiple myeloma relapse after autotransplant: optimal timing of immunotherapy. Cancer Immunol Res. 2016; 4(1): 61–71. DOI: 10.1158/2326-6066.CIR-15-0055.

19. Sun Y., Yang K., Bridal T., Ehrhardt A.G. Robust Ki67 detection in human blood by fl ow cytometry for clinical studies. Bioanalysis. 2016; 8(23): 2399–413. DOI: 10.4155/bio-2016-0194.

20. Jelinek T., Paiva B., Hajek R. Update on PD-1/PD-L1 inhibitors in multiple myeloma. Front Immunol. 2018; 9: 2431. DOI: 10.3389/fi mmu.2018.02431.

21. Tan J., Chen S., Huang J., et al. Increased exhausted CD8+ T cells with programmed death-1, T-cell immunoglobulin and mucin-domain-containing-3 phenotype in patients with multiple myeloma. Asia Pac J Clin Oncol. 2018; 14(5): e266–74. DOI: 10.1111/ajco.13033.

22. Li H., van der Leun A.M., Yofe I., et al. Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma. Cell. 2020; 181(3): 747. DOI: 10.1016/j.cell.2020.04.017.

23. Miller B.C., Sen D.R., Al Abosy R., et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol. 2019; 20(3): 326–36. DOI: 10.1038/s41590-019-0312-6.

24. Thommen D.S., Koelzer V.H., Herzig P., et al. A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-smallcell lung cancer treated with PD-1 blockade. Nat Med. 2018; 24: 994–1004. DOI: 10.1038/s41591-018-0057-z.

25. Ma J., Zheng B., Goswami S., et al. PD1Hi CD8+ T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma. J Immunother Сancer. 2019; 7(1): 331. DOI: 10.1186/s40425-019-0814-7.

26. Hastings W.D., Anderson D.E., Kassam N., et al. TIM-3 is expressed on activated human CD4+ T cells and regulates Th1 and Th17 cytokines. Eur J Immunol. 2009; 39(9): 2492–501. DOI: 10.1002/eji.200939274.

27. Li Z., Liu X., Guo R., Wang P. TIM-3 plays a more important role than PD-1 in the functional impairments of cytotoxic T cells of malignant Schwannomas. Tumour Biol. 2017; 39(5): 1010428317698352. DOI: 10.1177/1010428317698352.

28. Sakuishi K., Apetoh L., Sullivan J.M., et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010; 207(10): 2187–94. DOI: 10.1084/jem.20100643.

29. Goldrath A.W., Luckey C.J., Park R., et al. The molecular program induced in T cells undergoing homeostatic proliferation. Proc Natl Acad Sci USA. 2004;101(48): 16885–90. DOI: 10.1073/pnas.0407417101.


Review

For citations:


Batorov E.V., Sergeevicheva V.V., Aristova T.A., Sizikova S.A., Ushakova G.Y., Gilevich A.V., Shevela E.A., Ostanin A.A., Chernykh E.R. Expression of PD-1 and TIM-3 inhibitory checkpoint molecules by T-lymphocytes in early post-transplant period in multiple myeloma patients. Russian journal of hematology and transfusiology. 2021;66(4):499-511. (In Russ.) https://doi.org/10.35754/0234-5730-2021-66-4-499-511

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ISSN 0234-5730 (Print)
ISSN 2411-3042 (Online)