Immunophenotypic Evaluation of CD305 and CD85d in B-Cell Lymphoid Neoplasms

Official title

Immunophenotypic Evaluation of Inhibitory Immune Receptors CD305 and CD85d in B-Cell Lymphoid Neoplasms

Overview

Inhibitory immune receptors, including CD85d and CD305 (LAIR-1), act as immune checkpoint-like molecules. They contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that recruit SH2-domain phosphatases (e.g., SHP-1), which suppress cellular activation (7,8). CD85d is predominantly expressed in myeloid cells, including monocytes, macrophages, dendritic cells, and granulocytes. It is also differentially expressed on NK, T, B cells, and neutrophils. It is expressed at high levels in tumor cells, facilitating immune escape by promoting immune suppression, allowing for tumor evasion (9). CD85d is widely expressed across AML, so it is a top candidate, due to its traditional association with myeloid phenotypes and limited expression in normal haematopoiesis (10). It was reported to be expressed in B cells of CLL patients in contrast to normal B cells. Its expression in CLL patients denotes a distinctive feature, which may be acquired during malignant transformation (8). Therefore, CD85d may have significant prognostic, mechanistic, and therapeutic roles in hematologic malignancies (11). As a novel biomarker in solid malignant tumors to predict the prognosis of patients, upregulation of CD85d in tumors is associated with worse tumor phenotypes. Targeting CD85d may be an effective tool for targeted cancer therapy (12). Concerning CD305, it has been reported in about 60% of CLL patients and may be used as an effective prognostic marker to predict TTFT in CLL patients (13). Despite their potential clinical significance, the expression patterns of CD85d and CD305 across B-cell lymphoid neoplasms subtypes remain incompletely identified. Illustrating their role may help to determine TTFT, prognosis, therapeutic targeting, and refinement of B-cell neoplasms classification in line with WHO-HAEM5 standards.

Detailed description

B-cell lymphoproliferative disorders (B LPDs) constitute a wide spectrum of clonal B-cell neoplasms, ranging from indolent chronic illness to more aggressive hematologic malignancies. Clinically, patients may present with lymphadenopathy, splenomegaly, cytopenias, or, in chronic cases, may be diagnosed accidentally by the presence of lymphocytosis during routine complete blood counts, confirmed by immunophenotyping showing a monoclonal B-cell population (1).

According to the World Health Organization Classification of Haematolymphoid Tumours, 5th edition (WHO HAEM5), mature B-cell neoplasms are diagnosed by integrating morphology, immunophenotyping, cytogenetics, and molecular features. Major B-CLPD subtypes include chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), hairy cell leukemia (HCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) (2). Accurate immunophenotypic diagnosis is essential as it helps to identify distinct prognoses and therapeutic approaches.

B-cell acute lymphoblastic leukemia/lymphoma is the most common pediatric leukemia, representing about 85% of ALL cases in children and 75% in adults. B-cell acute lymphoblastic leukemia/lymphoma is a precursor B-lineage neoplasm comprising lymphoblasts that express CD19, CD22, CD79a, and/or PAX5, besides the expression of immaturity markers such as TdT and CD34, while lacking surface immunoglobulin expression (3-5). Its inclusion differentiates the spectrum of B-cell neoplasms from precursor to mature stages.

Management of asymptomatic patients with B-CLPDs commonly follows a "watch and wait" strategy, whereas B-ALL requires prompt therapeutic intervention. Prognostic indicators in B-CLPDs, such as genetic mutations detected by fluorescence in situ hybridization (FISH) (del(17p), del(11q), trisomy 12, del(13q)), IGHV gene somatic hypermutation status, and TP53 mutations, can guide risk stratification and predict time to first treatment (TTFT) (6).

Inhibitory immune receptors, including CD85d and CD305 (LAIR-1), act as immune checkpoint-like molecules. They contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that recruit SH2-domain phosphatases (e.g., SHP-1), which suppress cellular activation (7,8).

CD85d is predominantly expressed in myeloid cells, including monocytes, macrophages, dendritic cells, and granulocytes. It is also differentially expressed on NK, T, B cells, and neutrophils. It is expressed at high levels in tumor cells, facilitating immune escape by promoting immune suppression, allowing for tumor evasion (9).

CD85d is widely expressed across AML, so it is a top candidate, due to its traditional association with myeloid phenotypes and limited expression in normal haematopoiesis (10). It was reported to be expressed in B cells of CLL patients in contrast to normal B cells. Its expression in CLL patients denotes a distinctive feature, which may be acquired during malignant transformation (8). Therefore, CD85d may have significant prognostic, mechanistic, and therapeutic roles in hematologic malignancies (11).

As a novel biomarker in solid malignant tumors to predict the prognosis of patients, upregulation of CD85d in tumors is associated with worse tumor phenotypes. Targeting CD85d may be an effective tool for targeted cancer therapy (12).

Concerning CD305, it has been reported in about 60% of CLL patients and may be used as an effective prognostic marker to predict TTFT in CLL patients (13).

Despite their potential clinical significance, the expression patterns of CD85d and CD305 across B-cell lymphoid neoplasms subtypes remain incompletely identified. Illustrating their role may help to determine TTFT, prognosis, therapeutic targeting, and refinement of B-cell neoplasms classification in line with WHO-HAEM5 standards.

Primary outcome measures

• Detect the expression of both CD85d and CD305 in B-cell acute lymphoblastic leukemia/lymphoma and B CLPDs. [Time frame: Baseline]

Secondary outcome measures (1)

• Correlate the expression of CD85d and CD305 with different B-cell lymphoproliferative disorders subtypes and B-cell acute lymphoblastic leukemia/lymphoma. [Time frame: Baseline]

Eligibility criteria

Inclusion criteria

• \- Newly diagnosed cases of B-cell acute lymphoblastic leukemia/lymphoma or B CLPDs according to the WHO classification and established by morphology, immunophenotyping, and, if available, cytogenetic/molecular findings.

Exclusion criteria

• Patients diagnosed with hematologic malignancies other than B-cell acute lymphoblastic leukemia/lymphoma or B CLPDs.
• Patients who have received prior therapy, including chemotherapy or immunomodulatory treatment.
• Patients refused to sign informed consent.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Case-control

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Perbellini O, Falisi E, Giaretta I, Boscaro E, Novella E, Facco M, Fortuna S, Finotto S, Amati E, Maniscalco F, Montaldi A, Alghisi A, Aprili F, Bonaldi L, Paolini R, Scupoli MT, Trentin L, Ambrosetti A, Semenzato G, Pizzolo G, Rodeghiero F, Visco C. Clinical significance of LAIR1 (CD305) as assessed by flow cytometry in a prospective series of patients with chronic lymphocytic leukemia. Haematolo PMID 24415628
• Carosella ED, Rouas-Freiss N, Tronik-Le Roux D, Moreau P, LeMaoult J. HLA-G: An Immune Checkpoint Molecule. Adv Immunol. 2015;127:33-144. doi: 10.1016/bs.ai.2015.04.001. Epub 2015 May 27. PMID 26073983
• Colovai AI, Tsao L, Wang S, Lin H, Wang C, Seki T, Fisher JG, Menes M, Bhagat G, Alobeid B, Suciu-Foca N. Expression of inhibitory receptor ILT3 on neoplastic B cells is associated with lymphoid tissue involvement in chronic lymphocytic leukemia. Cytometry B Clin Cytom. 2007 Sep;72(5):354-62. doi: 10.1002/cyto.b.20164. PMID 17266150
• Mansouri L, Thorvaldsdottir B, Sutton LA, Karakatsoulis G, Meggendorfer M, Parker H, Nadeu F, Brieghel C, Laidou S, Moia R, Rossi D, Catherwood M, Kotaskova J, Delgado J, Rodriguez-Vicente AE, Benito R, Rigolin GM, Bonfiglio S, Scarfo L, Mattsson M, Davis Z, Gogia A, Rani L, Baliakas P, Foroughi-Asl H, Jylha C, Skaftason A, Rapado I, Miras F, Martinez-Lopez J, de la Serna J, Rivas JMH, Thornton P, PMID 36566271
• Kantarjian H, Jabbour E. Adult Acute Lymphoblastic Leukemia: 2025 Update on Diagnosis, Therapy, and Monitoring. Am J Hematol. 2025 Jul;100(7):1205-1231. doi: 10.1002/ajh.27708. Epub 2025 May 16. PMID 40377367
• Lejman M, Chalupnik A, Chilimoniuk Z, Dobosz M. Genetic Biomarkers and Their Clinical Implications in B-Cell Acute Lymphoblastic Leukemia in Children. Int J Mol Sci. 2022 Mar 2;23(5):2755. doi: 10.3390/ijms23052755. PMID 35269896
• Alaggio R, Amador C, Anagnostopoulos I, Attygalle AD, Araujo IBO, Berti E, Bhagat G, Borges AM, Boyer D, Calaminici M, Chadburn A, Chan JKC, Cheuk W, Chng WJ, Choi JK, Chuang SS, Coupland SE, Czader M, Dave SS, de Jong D, Du MQ, Elenitoba-Johnson KS, Ferry J, Geyer J, Gratzinger D, Guitart J, Gujral S, Harris M, Harrison CJ, Hartmann S, Hochhaus A, Jansen PM, Karube K, Kempf W, Khoury J, Kimura H, PMID 35732829
• Debord C, Wuilleme S, Eveillard M, Theisen O, Godon C, Le Bris Y, Bene MC. Flow cytometry in the diagnosis of mature B-cell lymphoproliferative disorders. Int J Lab Hematol. 2020 Jun;42 Suppl 1:113-120. doi: 10.1111/ijlh.13170. PMID 32543070

Identifiers

NCT: NCT07499635 · CD305 and CD85d

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗