Abstract
Objectives
Epstein-Barr virus–positive large B-cell lymphoma (EBV+ LBCL) is a heterogeneous group of diseases that may resemble classic Hodgkin lymphoma (CHL) both morphologically and immunophenotypically. However, these diseases are treated with different therapies and carry distinct prognoses. We examined CD200 expression by immunohistochemistry in EBV+ LBCL and evaluated its diagnostic utility in the differential diagnosis with CHL.
Methods
CD200 immunohistochemistry was performed on archival material from 20 cases of CHL (11 EBV+, 9 EBV−), 11 cases of EBV+ LBCL, and 10 cases of diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS). Staining pattern and intensity (0-3+ scale) were recorded.
Results
CD200 positivity was seen in Reed-Sternberg cells in 19 (95%) of 20 cases of CHL, predominantly in a strong (3+, 15/19) and diffuse (>50% of cells, 17/19) pattern. In contrast, CD200 was negative in 8 (73%) of 11 cases of EBV+ LBCL; the 3 positive cases showed 1 to 2+ staining in less than 50% of lesional cells. All cases of DLBCL NOS were negative for CD200.
Conclusions
CD200 may be a useful immunophenotypic marker in differentiating EBV+ LBCL from CHL, with negative to partial/weak staining favoring a diagnosis of EBV+ LBCL and strong diffuse staining favoring a diagnosis of CHL.
Keywords: CD200, EBV, Large B-cell lymphoma, Classic Hodgkin lymphoma
KEY POINTS.
Epstein-Barr virus–positive large B-cell lymphoma (EBV+ LBCL) may show overlapping morphologic and immunophenotypic features with classic Hodgkin lymphoma (CHL).
CD200 is positive in nearly all cases of CHL, while cases of EBV+ LBCL are predominantly negative for CD200.
CD200 immunohistochemistry may help in distinguishing EBV+ LBCL from CHL.
INTRODUCTION
Epstein-Barr virus–positive large B-cell lymphomas (EBV+ LBCLs) are a heterogeneous group of diseases that may occur in the setting of immunodeficiency or immunosuppression1 or in older patients with age-related immune senescence.2,3 In addition, these lymphomas are now also known to occur in younger patients with no known underlying immunodeficiency or immunosuppression.4-6 Epstein-Barr virus–positive LBCLs can show a range of morphologies: cases showing a “monomorphic” pattern contain a diffuse proliferation of monomorphic intermediate- to large-sized cells, resembling EBV-negative diffuse large B-cell lymphoma (DLBCL), whereas a greater percentage of cases show a “polymorphic” or “T-cell/histiocytic rich large B-cell lymphoma-like” histologic pattern, with a variable number of large neoplastic cells, often resembling Reed-Sternberg (RS) cells, within a mixed inflammatory background infiltrate.3,6,7 In addition to showing positivity for EBV-encoded RNA, neoplastic B cells typically retain positivity for multiple B-cell markers, show CD30 positivity in many cases, and may be positive for CD15 in a subset of cases.6,7 Epstein-Barr virus–positive LBCLs are considered aggressive B-cell lymphomas and are often treated with combination immunochemotherapy regimens, such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, with a 5-year overall survival of 55%.7
The morphologic features of “polymorphic”-type EBV+ LBCL may raise consideration of classic Hodgkin lymphoma (CHL).8 Classic Hodgkin lymphoma shows a bimodal age distribution, affecting younger patients in the second and third decades of life and showing a second peak in older patients.8 In contrast to the immunochemotherapy regimens used for EBV+ LBCL, CHL is commonly treated with ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine) and shows high response rates, with complete remission rates of approximately 90% to 95%.9 The neoplastic RS cells in CHL are classically negative for CD20 as well as other B-cell markers, which can help distinguish CHL from EBV+ LBCL in many cases. However, possibly related to newer antigen retrieval methods, CD20 expression may be seen in cases of CHL with increased frequency.8 Furthermore, downregulated or variable expression of CD20 is known to occur in EBV+ B-cell lymphoproliferative disorders.10-12 Therefore, given overlapping histologic and immunophenotypic profiles, differentiation between EBV+ LBCL and CHL may be challenging in some cases.
Previous work has shown that RS cells in CHL express CD200,13 while CD200 is largely negative in DLBCL, not otherwise specified (NOS).13-15 CD200 (OX-2 antigen) is a transmembrane glycoprotein within the type I immunoglobulin superfamily that is normally expressed in multiple different cell types, including B lymphocytes, a subset of T lymphocytes, dendritic cells, endothelial cells, and neurons.1 Interaction between CD200 and its receptor, CD200R, induces immunosuppressive signaling through suppression of macrophage16,17 and antitumor T-cell18,19 and natural killer (NK)–cell20 function and induction of regulatory T cells.21 Indeed, CD200 expression has been associated with an adverse prognosis in multiple myeloma22 and acute myeloid leukemia.23,24 While CD200 expression has been examined in a wide range of B-cell malignancies,13 the pattern of CD200 expression in EBV+ LBCL is unknown. Therefore, we examined CD200 expression in EBV+ LBCL and evaluated its diagnostic utility in the differential diagnosis with CHL.
MATERIALS AND METHODS
Case Selection
Cases were retrieved from the archives at Vanderbilt University Medical Center following institutional review board approval. Pathologic diagnoses were established using the 2016 revised World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues1 using morphologic features, immunohistochemical and in situ hybridization studies, and cytogenetic analysis, as applicable. All cases were reviewed and the diagnoses confirmed by both authors. Clinical information was collected from the electronic medical record.
Immunohistochemistry
CD200 immunohistochemistry was performed on 5-μm formalin-fixed, paraffin-embedded tissue sections. Staining was performed on a Leica Bond-Max (Leica Biosystems) following antigen retrieval (EDTA pH 9.0, 20 minutes) with a goat anti-human CD200 polyclonal antibody (AF2724; R&D Systems) at a 1:150 dilution. Secondary detection was performed using a rabbit anti-goat antibody (BA5000; Vector Laboratories). CD200 expression pattern and staining intensity (0 to 3+ scale; Supplemental Figure 1; all supplemental materials can be found at American Journal of Clinical Pathology online) were recorded.
Statistical Analysis
Fisher exact tests were used to calculate statistical significance for categorical variables. P ≤ .05 was considered statistically significant.
RESULTS
CD200 expression was evaluated in a total of 41 cases Figure 1, including 20 cases of CHL, with 11 EBV-positive cases and 9 EBV-negative cases. These included 13 cases of nodular sclerosis CHL and 7 cases of mixed-cellularity disease. Patients with CHL showed a median age at diagnosis of 36.5 years (range, 13-70 years). The cohort also included 11 cases of EBV+ LBCL, with patients showing a median age at diagnosis of 67 years (range, 43-83 years). The morphology of the EBV+ LBCL cases ranged from diffuse infiltrates with sheets of neoplastic cells to nodular infiltrates with fibrosis and scattered neoplastic cells admixed within a mixed inflammatory background. Finally, 10 cases of DLBCL NOS, with a median age at diagnosis of 66.5 years (range, 48-77 years), were included. Five patients had a history of HIV infection, including 3 patients with CHL and 2 patients with EBV+ LBCL.
FIGURE 1.
CD200 staining in Hodgkin and large B-cell lymphoma (LBCL). Bar graph showing the percentage of cases in each diagnostic category with CD200 staining. In classic Hodgkin lymphoma (CHL), CD200 positivity was seen in Reed-Sternberg cells in 19 (95%) of 20 cases, with a predominance of strong (3+) staining (15/19; 79%). CD200 was negative in 8 (73%) of 11 cases of Epstein-Barr virus–positive (EBV+) LBCL; the 3 positive cases showed dim or moderate (1-2+) staining. All tested cases of diffuse LBCL (DLBCL) not otherwise specified (NOS) were negative for CD200 staining.
CD200 positivity was seen in RS cells in 19 (95%) of 20 cases of CHL, predominantly in a strong (3+; 15/19 cases) and diffuse (>50% of cells; 17/19 cases) staining pattern, with membranous (7/19 cases) or both membranous and Golgi (12/19 cases) staining Figure 2. In contrast, CD200 was negative in 8 (73%) of 11 cases of EBV+ LBCL. The 3 cases with positive staining showed weak to moderate (1-2+) membranous staining in less than 50% of lesional cells. All 10 cases of DLBCL NOS were negative for CD200. When specifically examining EBV+ cases, including 11 cases of EBV+ CHL and 11 cases of EBV+ LBCL, CD200 positivity was statistically significantly more common in EBV+ CHL (10/11; 91%) than in EBV+ LBCL (3/11; 27%) (P = .008). Importantly, the characteristic RS cell immunophenotype of positivity for CD30 and CD15 and negativity for CD20 and CD45 was seen in only 4 (36%) of 11 cases of EBV+ CHL Table 1. Furthermore, CD200 positivity in EBV+ CHL was more common than CD15 positivity (7/11; 64%) and CD20 negativity (5/11; 45%). CD200 aided in differentiating EBV+ CHL with frequent RS cells from EBV+ LBCL Figure 3. Similarly, CD200 was helpful in differentiating EBV+ LBCL with rare neoplastic cells from EBV+ CHL Figure 4. Consistent with previous work,13 CD200 positivity was seen in background follicular dendritic cells and in endothelial cells across diagnostic categories.
FIGURE 2.
Representative CD200 staining in Hodgkin and large B-cell lymphoma (LBCL). Representative images of H&E-stained sections and immunohistochemical stains for cases in each diagnostic category. All images ×400. CHL, classic Hodgkin lymphoma; DLBCL, diffuse large B-cell lymphoma; EBV, Epstein-Barr virus; NOS, not otherwise specified.
TABLE 1.
Immunophenotypic features of EBV+ CHL and EBV+ LBCL
| Case | CD200 Intensity/% + Cells | CD20 | PAX5 | CD30 | CD15 | CD45 |
|---|---|---|---|---|---|---|
| EBV+ CHL | ||||||
| 1 | 3+/>75% | – | + very weak | + | +/– | – |
| 2 | – | –/+ | + weak | + | –/+ | –/+ |
| 3 | 3+/25%-50% | –/+ | + weak | + | + | – |
| 4 | 3+/>75% | –/+ | + | + | – | – |
| 5 | 3+/>75% | +/– | + | + | – | ND |
| 6 | 3+/>75% | – | + weak | + | + | – |
| 7 | 2+/>75% | –/+ | + weak | + weak | –/+ | – |
| 8 | 2+/50%-75% | + | + weak | + weak | – | –/+ |
| 9 | 3+/>75% | – | + | + weak | – | – |
| 10 | 3+/>75% | – | + weak | + weak | + | – |
| 11 | 3+/>75% | – | + very weak | + | + | ND |
| EBV+ LBCL | ||||||
| 1 | 2+/50% | +/– | + | + | – | –/+ |
| 2 | – | + | ND | + | ND | ND |
| 3 | 2+/<25% | + | ND | ND | ND | ND |
| 4 | – | + | ND | ND | ND | ND |
| 5 | – | + | + | –/+ | – | + |
| 6 | 1+/25%-50% | + | + weak | + | – | –/+ |
| 7 | – | + | ND | ND | ND | ND |
| 8 | – | +/– | + very weak | + | ND | + |
| 9 | – | + | ND | – | ND | ND |
| 10 | – | + | ND | + | ND | ND |
| 11 | – | + | ND | ND | ND | ND |
CHL, classic Hodgkin lymphoma; EBV, Epstein-Barr virus; LBCL, large B-cell lymphoma; ND, no data; +, positive; –, negative; +/–, variable staining, more positive cells than negative cells; –/+, variable staining, more negative cells than positive cells.
FIGURE 3.
CD200 can help differentiate Epstein-Barr virus−positive (EBV+) classic Hodgkin lymphoma (CHL) with frequent Reed-Sternberg (RS) cells and EBV+ large B-cell lymphoma (LBCL). Representative images of H&E-stained sections and immunohistochemical stains for a case of EBV+ (CHL) with frequent RS cells and a case of EBV+ LBCL. In both cases, lesional cells were positive for CD30 and EBER and showed variable positivity for CD20. However, CD200 was positive in the case of EBV+ CHL and negative in the case of EBV+ LBCL. All images ×400.
FIGURE 4.
CD200 can help differentiate Epstein-Barr virus−positive (EBV+) large B-cell lymphoma (LBCL) with rare neoplastic cells from EBV+ classic Hodgkin lymphoma (CHL). Representative images of H&E-stained sections and immunohistochemical stains for a case of EBV+ CHL and a case of EBV+ LBCL with rare neoplastic cells and CHL-like morphology. In both cases, lesional cells were weakly positive for CD20 and CD30. However, CD200 was positive in the case of EBV+ CHL and negative in the case of EBV+ LBCL (arrows). All images ×600.
A single case of CHL was negative for CD200. The case occurred in a 54-year-old man with HIV/AIDS (absolute CD4 count of 39/mm3 at the time of lymphoma diagnosis) who had diffuse intensely fluorodeoxyglucose (FDG)-avid lymphadenopathy above and below the diaphragm, with bulky retroperitoneal and abdominal lymphadenopathy, as well as splenomegaly with intense FDG uptake in the spleen. An excisional biopsy specimen of an inguinal lymph node Figure 5 showed effacement of nodal architecture by a mixed inflammatory infiltrate composed of small lymphocytes, histiocytes, plasma cells, and rare eosinophils. Admixed were frequent large, abnormal cells with prominent nucleoli, including occasional cells with RS morphology. The malignant cells were positive for EBV by in situ hybridization, were strongly positive for CD30, and showed weak PAX5 expression. CD20 and CD15 were positive in rare large cells. CD45 was positive in a subset of the malignant cells. A diagnosis of EBV+ CHL was made. However, the patient was refractory to ABVD therapy and to 2 cycles of salvage ifosfamide, carboplatin, and etoposide (ICE) chemotherapy and ultimately died of his disease. Therefore, the clinicopathologic findings, in conjunction with the CD200 negativity, raise the possibility that this case may have been best classified as EBV+ LBCL rather than EBV+ CHL.
FIGURE 5.
A single case of CD200-negative classic Hodgkin lymphoma (CHL). The single case of CHL in which Reed-Sternberg cells were negative for CD200 was Epstein-Barr virus positive (EBV+), HIV associated, and refractory to CHL-directed therapy, raising the possibility that this may in fact have represented EBV+ large B-cell lymphoma. Arrows highlight large abnormal cells that show weak positivity for PAX5 (B) and variable positivity for CD20 (C) and are negative for CD200 (F). A, H&E. D, CD30. E, EBER. All images ×400.
DISCUSSION
Epstein-Barr virus–positive LBLC and CHL can show overlapping morphologic and immunophenotypic features. However, differentiating between these entities is critical, as they are treated with distinct therapies and carry different prognoses. Consistent with prior reports,13 CD200 was positive in 95% of CHL cases in our cohort, including cases where RS cells showed positivity for CD20 or were negative for CD15. Most CHL cases showed strong, diffuse CD200 expression in RS cells. In contrast, CD200 was positive in only 3 of 11 cases of EBV+ LBCL, with these cases showing weak to moderate expression in a subset of cells. Overall, our findings suggest that CD200 may be a useful immunophenotypic marker in differentiating EBV+ LBCL from CHL, with negative to partial/weak staining favoring a diagnosis of EBV+ LBCL and strong, diffuse staining favoring CHL. At a time when noninvasive core biopsies are increasingly common and pathologists may get only a limited sample of lesional tissue, CD200 immunohistochemistry provides an additional tool in distinguishing these lymphomas with varying and overlapping characteristics.
Interaction between CD200 and CD200R elicits immunosuppressive signaling, downregulating macrophage, NK-cell, and T-cell function.16-21,25 In addition to the potential diagnostic utility shown here, the strong and diffuse CD200 expression in CHL may hold therapeutic potential as well. A phase 1, first-in-human study of samalizumab, a humanized monoclonal antibody targeting CD200 in patients with chronic lymphocytic leukemia and multiple myeloma,26 showed decreased tumor burden in 14 of 23 patients, with 16 of 23 patients showing stable disease, with overall mild to moderate adverse events. Extension of these studies to CHL, where RS cells not only express high levels of CD200 but also exist in a dense reactive inflammatory background, appears warranted. Indeed, studies have shown high response rates for other immune checkpoint therapies for CHL, including therapies targeting the PD-1/PD-L1 axis.9 PD-L1 is strongly expressed on lesional cells in both CHL and EBV+ LBCL,27 suggesting that anti–PD-1 therapies may be effective in EBV+ LBCL as well. Studies addressing this question are currently ongoing (NCT03258567; NCT03038672).
Recent work15 examining CD200 expression in the context of posttransplant lymphoproliferative disorders (PTLDs) found CD200 to be positive in 9 (24%) of 38 PTLDs, all of which represented monomorphic PTLDs presenting as DLBCL (PTLD-DLBCL), including 6 cases that were positive for EBV. These authors found that 30% of EBV+ PTLD-DLBCL cases showed CD200 positivity. While we found a similar percentage (27%) of EBV+ LBCL cases showing CD200 positivity, EBV+ LBCL cases in our cohort showed weak to moderate staining in less than 50% of cells, whereas Vaughan et al15 reported strong staining in more than 50% of lesional cells in all cases of EBV+ PTLD-DLBCL. Furthermore, these authors showed approximately 30% CD200 positivity in EBV-negative PTLD-DLBCL but report that only 8% of de novo DLBCL cases in their cohort showed CD200 positivity, similar to our findings and to previous work.13,14 Taken together, these results suggest that the immune environment within DLBCL presenting as PTLD, whether EBV positive or EBV negative, may be distinct from that in de novo cases. Interestingly, in addition to the patient in our cohort described in Figure 4, 2 additional patients in our EBV+ LBCL cohort had HIV. All 3 of these patients had CD200-negative disease. Therefore, the increased CD200 expression seen in PTLD-DLBCL may stem from features specific to the posttransplant setting, rather than from a generally immunosuppressed environment.
Previous work has shown significant CD200 expression in follicular dendritic cells and endothelial cells, which was seen in this study as well. Therefore, careful analysis may be required in some cases to differentiate background staining from true expression on malignant cells. Nonetheless, our findings demonstrate the diagnostic utility of CD200 immunohistochemistry in differentiating between EBV+ B-cell lymphomas.
Supplementary Material
Acknowledgments
This work was supported by CTSA award No. UL1 TR002243 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health (NIH). We thank the Translational Pathology Shared Resource supported by National Cancer Institute/NIH Cancer Center Support Grant 5P30 CA68485-19. Immunohistochemical studies were supported by the Shared Instrumentation Grant S10 OD023475-01A1.
Contributor Information
Christopher Batuello, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, US.
Emily F Mason, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, US.
Conflict of interest disclosure
The authors have nothing to disclose.
REFERENCES
- 1. Swerdlow SH, Campo E, harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Rev 4th ed. IARC; 2017. [Google Scholar]
- 2. Oyama T, Ichimura K, Suzuki R, et al. Senile EBV+ B-cell lymphoproliferative disorders: a clinicopathologic study of 22 patients. Am J Surg Pathol. 2003;27:16-26. 10.1097/00000478-200301000-00003 [DOI] [PubMed] [Google Scholar]
- 3. Oyama T, Yamamoto K, Asano N, et al. Age-related EBV-associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: a study of 96 patients. Clin Cancer Res. 2007;13:5124-5132. 10.1158/1078-0432.CCR-06-2823 [DOI] [PubMed] [Google Scholar]
- 4. Hong JY, Yoon DH, Suh C, et al. EBV-positive diffuse large B-cell lymphoma in young adults: is this a distinct disease entity? Ann Oncol. 2015;26:548-555. 10.1093/annonc/mdu556 [DOI] [PubMed] [Google Scholar]
- 5. Uccini S, Al-Jadiry MF, Scarpino S, et al. Epstein-Barr virus-positive diffuse large B-cell lymphoma in children: a disease reminiscent of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly. Hum Pathol. 2015;46:716-724. 10.1016/j.humpath.2015.01.011 [DOI] [PubMed] [Google Scholar]
- 6. Nicolae A, Pittaluga S, Abdullah S, et al. EBV-positive large B-cell lymphomas in young patients: a nodal lymphoma with evidence for a tolerogenic immune environment. Blood. 2015;126:863-872. 10.1182/blood-2015-02-630632 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Bourbon E, Maucort-Boulch D, Fontaine J, et al. Clinicopathological features and survival in EBV-positive diffuse large B-cell lymphoma not otherwise specified. Blood Adv. 2021;5:3227-3239. 10.1182/bloodadvances.2021004515 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Wang HW, Balakrishna JP, Pittaluga S, Jaffe ES.. Diagnosis of Hodgkin lymphoma in the modern era. Br J Haematol. 2019;184:45-59. 10.1111/bjh.15614 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Ansell SM. Hodgkin lymphoma: a 2020 update on diagnosis, risk-stratification, and management. Am J Hematol. 2020;95:978-989. 10.1002/ajh.25856 [DOI] [PubMed] [Google Scholar]
- 10. Shimoyama Y, Yamamoto K, Asano N, Oyama T, Kinoshita T, Nakamura S.. Age-related Epstein-Barr virus-associated B-cell lymphoproliferative disorders: special references to lymphomas surrounding this newly recognized clinicopathologic disease. Cancer Sci. 2008;99:1085-1091. 10.1111/j.1349-7006.2008.00813.x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Dojcinov SD, Venkataraman G, Raffeld M, Pittaluga S, Jaffe ES.. EBV positive mucocutaneous ulcer—a study of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol. 2010;34:405-417. 10.1097/PAS.0b013e3181cf8622 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Elsayed AA, Satou A, Eladl AE, Kato S, Nakamura S, Asano N.. Grey zone lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma: a clinicopathological study of 14 Epstein-Barr virus-positive cases. Histopathology. 2017;70:579-594. 10.1111/his.13100 [DOI] [PubMed] [Google Scholar]
- 13. Dorfman DM, Shahsafaei A.. CD200 (OX-2 membrane glycoprotein) expression in B cell-derived neoplasms. Am J Clin Pathol. 2010;134:726-733. 10.1309/AJCP38XRRUGSQOVC [DOI] [PubMed] [Google Scholar]
- 14. Dorfman DM, Shahsafaei A, Alonso MA.. Utility of CD200 immunostaining in the diagnosis of primary mediastinal large B cell lymphoma: comparison with MAL, CD23, and other markers. Mod Pathol. 2012;25:1637-1643. 10.1038/modpathol.2012.129 [DOI] [PubMed] [Google Scholar]
- 15. Vaughan JW, Shi M, Horna P, Olteanu H.. Increased CD200 expression in post-transplant lymphoproliferative disorders correlates with an increased frequency of FoxP3(+) regulatory T cells. Ann Diagn Pathol. 2020;48:151585. 10.1016/j.anndiagpath.2020.151585 [DOI] [PubMed] [Google Scholar]
- 16. Wright GJ, Puklavec MJ, Willis AC, et al. Lymphoid/neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function. Immunity. 2000;13:233-242. 10.1016/s1074-7613(00)00023-6 [DOI] [PubMed] [Google Scholar]
- 17. Hoek RM, Ruuls SR, Murphy CA, et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science. 2000;290:1768-1771. 10.1126/science.290.5497.1768 [DOI] [PubMed] [Google Scholar]
- 18. Gorczynski RM, Cattral MS, Chen Z, et al. An immunoadhesin incorporating the molecule OX-2 is a potent immunosuppressant that prolongs allo- and xenograft survival. J Immunol. 1999;163(3):1654-1660. https://www.ncbi.nlm.nih.gov/pubmed/10415071. [PubMed] [Google Scholar]
- 19. Coles SJ, Hills RK, Wang EC, et al. Increased CD200 expression in acute myeloid leukemia is linked with an increased frequency of FoxP3+ regulatory T cells. Leukemia. 2012;26:2146-2148. 10.1038/leu.2012.75 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Coles SJ, Wang EC, Man S, et al. CD200 expression suppresses natural killer cell function and directly inhibits patient anti-tumor response in acute myeloid leukemia. Leukemia. 2011;25:792-799. 10.1038/leu.2011.1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Gorczynski RM, Lee L, Boudakov I.. Augmented Induction of CD4+CD25+ Treg using monoclonal antibodies to CD200R. Transplantation. 2005;79(9):1180-1183. https://www.ncbi.nlm.nih.gov/pubmed/15880066 [PubMed] [Google Scholar]
- 22. Moreaux J, Hose D, Reme T, et al. CD200 is a new prognostic factor in multiple myeloma. Blood. 2006;108:4194-4197. 10.1182/blood-2006-06-029355 [DOI] [PubMed] [Google Scholar]
- 23. Tonks A, Hills R, White P, et al. CD200 as a prognostic factor in acute myeloid leukaemia. Leukemia. 2007;21:566-568. 10.1038/sj.leu.2404559 [DOI] [PubMed] [Google Scholar]
- 24. Kandeel EZ, Madney Y, Eldin DN, Shafik NF.. Overexpression of CD200 and CD123 is a major influential factor in the clinical course of pediatric acute myeloid leukemia. Exp Mol Pathol. 2021;118:104597. 10.1016/j.yexmp.2020.104597 [DOI] [PubMed] [Google Scholar]
- 25. D’Arena G, De Feo V, Pietrantuono G, et al. CD200 and chronic lymphocytic leukemia: biological and clinical relevance. Front Oncol. 2020;10:584427. 10.3389/fonc.2020.584427 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Mahadevan D, Lanasa MC, Farber C, et al. Phase I study of samalizumab in chronic lymphocytic leukemia and multiple myeloma: blockade of the immune checkpoint CD200. J ImmunoTher Cancer. 2019;7:227. 10.1186/s40425-019-0710-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res. 2013;19:3462-3473. 10.1158/1078-0432.CCR-13-0855 [DOI] [PMC free article] [PubMed] [Google Scholar]
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