Do PD-1 and PD-L2 expressions have prognostic impact in hematologic malignancies?
Do PD-1 and PD-L2 expressions have prognostic impact in hematologic malignancies?
Background/aim: PD-1 (programmed death-1) is an immune checkpoint receptor that modulates T-cell activity in peripheral tissuesvia interaction with its ligands, PD-L1 (programmed death-ligand 1) and PD-L2 (programmed death-ligand 2). Tumor cells upregulatePD-L1 or PD-L2 to inhibit this T lymphocyte attack. Our goal was to determine the PD-1 and PD-L2 expression rates of varioushematologic malignancies, and evaluate whether PD-1 and PD-L2 expressions have an impact on prognosis.Materials and methods: For this purpose, pretreatment bone marrow biopsy specimens of 83 patients [42 multiple myeloma (MM),21 acute leukemia, and 20 chronic lymphocytic leukemia (CLL)] were stained with monoclonal antibody immunostains of PD-1 andPD-L2.Results: As a result, the overall expression rate of PD-1 was 26.2%, 4.8%, and 60% in patients with MM, acute leukemia, and CLL,respectively, whereas the PD-L2 expression rate was 61.9%, 14.3%, and 10% in patients with MM, acute leukemia, and CLL, respectively.Conclusion: Finally, we concluded that the role of the PD-1 pathway can be demonstrated by immunohistochemistry (IHC). Since weevaluated whether there is a correlation between the (IHC) results and survival of patients with MM, acute leukemia, and CLL, we couldnot demonstrate meaningful evidence that these markers have an impact on prognosis.
___
- 1. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-
H1 (PD-L1) pathway to activate anti-tumor immunity. Curr
Opin Immunol 2012; 24: 207-212.
- 2. Pardoll DM. The blockade of immune checkpoints in cancer
immunotherapy. Nat Rev Cancer 2012; 12: 252-264.
- 3. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ.
Programmed death-1 ligand 1 interacts specifically with
the B7-1 costimulatory molecule to inhibit T cell responses.
Immunity 2007; 27: 111-122.
- 4. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman
GJ, Kuchroo VK, Sharpe AH. PD-L1 regulates the development,
maintenance, and function of induced regulatory T cells. J Exp
Med 2009; 206: 3015-3029.
- 5. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC,
McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins
MB et al. Safety, activity, and immune correlates of anti-PD-1
antibody in cancer. N Engl J Med 2012; 366: 2443-2454.
- 6. Zou W, Chen L. Inhibitory B7-family molecules in the tumor
micro environment. Nat Rev Immunol 2008; 8: 467-477.
- 7. Guo Y, Feng X, Jiang Y, Shi X, Xing X, Liu X, Li N, Fadeel
B, Zheng C. PD1 blockade enhances cytotoxicity of in
vitro expanded natural killer cells towards myeloma cells.
Oncotarget 2016; 7: 48360-48374.
- 8. Sponaas AM, Moharrami NN, Feyzi E, Standal T, Holth Rustad
E, Waage A, Sundan A. PDL1 Expression on Plasma and
Dendritic Cells in Myeloma Bone Marrow Suggests Benefit
of Targeted anti PD1-PDL1 Therapy. PLoS One 2015; 10:
e0139867.
- 9. Salih HR, Wintterle S, Krusch M, Kroner A, Huang YH, Chen
L, Wiendl H. The role of leukemia-derived B7-H1 (PD-L1) in
tumor-T-cell interactions in humans. Exp Hematol 2006; 34:
888-894.
- 10. Chen X, Liu S, Wang L, Zhang W, Ji Y, Ma X. Clinical
significance of B7-H1 (PD-L1) expression in human acute
leukemia. Cancer Biol Ther 2008; 7: 622-627.
- 11. Ramsay AG, Clear AJ, Fatah R, Gribben JG. Multiple inhibitory
ligands induce impaired T-cell immunologic synapse function
in chronic lymphocytic leukemia that can be blocked with
lenalidomide: establishing a reversible immune evasion
mechanism in human cancer Blood 2012; 120: 1412-1421.
- 12. 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: 678-687.
- 13. Riches JC, Davies JK, McClanahan F, Fatah R, Iqbal S, Agrawal
S, Ramsay AG, Gribben JG. T cells from CLL patients exhibit
features of T-cell exhaustion but retain capacity for cytokine
production. Blood 2013; 121: 1612-1621.
- 14. Ribas A. Tumor immunotherapy directed at PD-1. N Engl J
Med 2012; 366: 2517-2519.
- 15. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its
ligands in tolerance and immunity. Annu Rev Immunol 2008;
26: 677-704.
- 16. Okazaki T, Honjo T. The PD-1-PD-L pathway in immunological
tolerance. Trends Immunol 2006; 27: 195-201.
- 17. Benson DM Jr., Bakan CE, Mishra A, Hofmeister CC, Efebera
Y, Becknell B, Baiocchi RA, Zhang J, Yu J, Smith MK et al.
The PD-1/PD-L1 axis modulates the natural killer cell versus
multiple myeloma effect: a therapeutic target for CT-011, a
novel monoclonal anti-PD-1 antibody. Blood 2010; 116: 2286-
2294.
- 18. Hallett WH, Jing W, Drobyski WR, Johnson BD.
Immunosuppressive effects of multiple myeloma are overcome
by PD-L1 blockade. Biol Blood Marrow Transplant 2011; 17:
1133-1145.
- 19. Paiva B, Azpilikueta A, Puig N, Ocio EM, Sharma R, Oyajobi
BO, Labiano S, San-Segundo L, Rodriguez A, Aires-Mejia I
et al. PD-L1/PD–1 presence in the tumor microenvironment
and activity of PD–1 blockade in multiple myeloma. Leukemia
2015; 29: 2110-2113.
- 20. Tamura H, Dan K, Tamada K, Nakamura K, Shioi Y, Hyodo H,
Wang SD, Dong H, Chen L, Ogata K. Expression of Functional
B7-H2 and B7.2 Costimulatory molecules and their prognostic
implications in de novo acute myeloid leukemia. Clin Cancer
Res 2005; 11: 5708-5717.
- 21. Brusa D, Serra S, Coscia M, Rossi D, D’Arena G, Laurenti L,
Jaksic O, Fedele G, Inghirami G, Gaidano G et al. The PD-1/
PD-L1 axis contributes to T-cell dysfunction in chronic
lymphocytic leukemia. Haematologica 2013; 98: 953-963.
- 22. Rusak M, Eljaszewicz A, Bołkun Ł, Łuksza E, Łapuć I, Piszcz
J, Singh P, Dąbrowska M, Bodzenta-Łukaszyk A, Kłoczko J et
al. Prognostic significance of PD-1 expression on peripheral
blood CD4+ T cells in patients with newly diagnosed chronic
lymphocytic leukemia. Pol Arch Med Wewn 2015; 125: 553-
559.
- 23. Grzywnowicz M, Zaleska J, Mertens D, Tomczak W, Wlasiuk
P, Kosior K, Piechnik A, Bojarska-Junak A, Dmoszynska
A, Giannopoulos K. Programmed death-1 and its ligand are
novel immunotolerant molecules expressed on leukemic B
cells in chronic lymphocytic leukemia. PLoS One 2012; 7:
e35178.
- 24. Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller
A, Leiba M, Koren-Michowitz M, Shimoni A, Nagler A. Phase
I safety and pharmacokinetic study of CT-011, a humanized
antibody interacting with PD-1, in patients with advanced
hematologic malignancies. Clin Cancer Res 2008; 14: 3044-
3051.
- 25. Suen H, Brown R, Yang S, Ho PJ, Gibson J, Joshua D. The
failure of immune checkpoint blockade in multiple myeloma
with PD-1 inhibitors in a phase 1 study. Leukemia 2015; 29:
1621-1622.
- 26. Lesokhin A, Ansell S, Armand P, Scott EC, Halwani A,
Gutierrez M, Millenson MM, Cohen AD, Schuster SJ, Lebovic
D et al. Nivolumab in patients with relapsed or refractory
hematologic malignancy: preliminary results of a phase ib
study. J Clin Oncol 2016; 34: 2698-2704.