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776 CD25-Dependent Feedback Control of the B-Cell Receptor and Its Oncogenic Mimics in B-Cell Malignancies

Program: Oral and Poster Abstracts
Type: Oral
Session: 622. Lymphoma Biology—Non-Genetic Studies: Other Lymphoma Types
Hematology Disease Topics & Pathways:
Follicular Lymphoma, ALL, Diseases, Biological, Therapies, Mantle Cell Lymphoma, Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Biological Processes, B-Cell Lymphoma, immunotherapy, Lymphoid Malignancies, Clinically relevant, signal transduction
Monday, December 3, 2018: 3:00 PM
Room 28D (San Diego Convention Center)

Jae-Woong Lee, PhD1*, Kohei Kume, PhD1*, Zhengshan Chen, MD-PhD1*, Gang Xiao, PhD1*, Kadriye Nehir Cosgun, PhD1*, Lai N Chan1*, Chun-Wei Chen, PhD1, Raju Pillai, MD2*, Wing C Chan, MD§2*, Stephen J Forman3, Larry W Kwak, MD, PhD4, Francesca Zammarchi, PhD5*, Patrick Van Berkel, PhD5*, David M Weinstock, MD6, Ari M Melnick, MD7, Vu N Ngo, PhD1*, Huimin Geng, PhD8, Selina Luger, MD9, Mark R. Litzow, MD10, Alexandre Belot, MD-PhD11*, Gulbu Uzel, MD12*, Michael T McManus, PhD13*, Elisabeth M. Paietta, PhD14*, Eric Meffre, PhD15* and Markus Muschen, MD1,16,17

1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, CA
2Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA
3Department of Hematology/HCT, City of Hope, Duarte, CA
4Toni Stephenson Lymphoma Center, City of Hope Comprehensive Cancer Center, Duarte, CA
5ADC Therapeutics Limited, London, United Kingdom
6Dana Farber Cancer Institute and Harvard Medical School, Boston, MA
7Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, NY
8Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA
9Division of Hematology-Oncology/Department of Medicine, University of Pennsylvania, Philadelphia, PA
10Division of Hematology, Mayo Clinic, Rochester, MN
11INSERM UMR, Université de Lyon, Lion, France
12NIAID National Institutes of Health, Bethesda, MD
13Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA
14Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY
15Department of Immunobiology, Yale University School of Medicine, New Haven, CT
16Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia CA, San Francisco, CA
17Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia CA, Monrovia, CA

Studying gene expression and clinical outcome data from 136 clinical trials for patients with cancer (~21,000 patients with 26 cancer types), we found CD25 as one of the strongest predictors of poor clinical outcome in patients with B-cell malignancies, but not in other cancer types. This was unexpected because CD25 is known as one of three chains of the IL2 receptor on T-cells and NK-cells.

Interleukin-2 (IL2) functions as essential T-cell growth factor. IL2 signals through β- and γ-, but not α-chains (CD25) of its heterotrimeric receptor. CD25-deficiency causes lymphoproliferation and autoimmunity, however, its mechanistic role is unclear. Our experiments based on genetic mouse models and engineered patient-derived B-cell leukemia and lymphoma xenografts revealed that CD25 expressed on B-cells is not an IL2 receptor chain, but in fact binds the B-cell receptor (BCR) to regulate its activity. Suggesting IL2-independent functions, defects in CD25-/- B-cells were not replicated in IL2-deficient mice. CD25 bound the BCR but not IL2Rβ- and IL2Rγ-chains. IL2Rβ- and IL2Rγ-chains can pair with other chains to form receptors for different cytokine-ligands. However, CD25 represents the first example of a cytokine receptor chain that binds to the BCR for negative feedback regulation.

Likewise, in T-cells, CD25 had a bifunctional role and either functioned as IL2 receptor chain or as negative feedback regulator of T-cell receptor signaling. CD25-function was regulated by cell-membrane translocation, which required phosphorylation of its cytoplasmic tail at S268 (see schematic, left). In a family with monogenic autoimmunity, a mutation immediately preceding S268 compromised CD25-surface translocation, which was restored by homology-directed repair of the S268 motif. CD25-interactome analyses identified PKCd as critical effector molecule downstream of CD25 to mediate B-cell selection during normal B-cell development and calibrate oncogenic BCR signaling in B-cell tumors.

In B-cell malignancies, BCR-dependent survival and proliferation signals are often substituted by oncogenic BCR-mimics (e.g. BCR-ABL1, JAK2, BRAFV600E, LMP2A, CD79B mutations; see schematic, right). Accordingly, we identified CD25 surface-expression as biomarker of oncogenic BCR-signaling and predictor of poor clinical outcomes. CD25-/- B-cell leukemia failed to initiate fatal disease in transplant recipients. Owing to imbalances of oncogenic BCR-signaling and p53-checkpoint activation, CD25-/- B-cell leukemia failed to initiate fatal disease in transplant recipients. In patient-derived xenograft models of drug-resistant B-cell malignancies, treatment with a CD25-specific antibody drug-conjugate (ADCT-301) extended survival of transplant recipients or eradicated disease. These findings identified CD25 as previously unrecognized feedback regulator of oncogenic BCR-signaling and provide a rationale for therapeutic targeting of CD25 in refractory B-cell malignancies.

Disclosures: Lee: City Of Hope: Employment; ADC Therapuetics: Other: ADCT-301 (CD25-ADC), Research Funding. Forman: Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Weinstock: Genentech/Roche, Monsanto: Consultancy; Novartis: Consultancy, Research Funding; Novartis, Astra Zeneca, Abbvie, Aileron, Surface Oncology, Daiichi Sankyo: Research Funding; Novartis, Dragonfly, Travera, DxTerity, Travera: Consultancy; Travera: Equity Ownership; Astra Zeneca, JAX, Samumed, Regeneron, Sun Pharma, Prescient: Patents & Royalties. Uzel: Novartis: Research Funding.

*signifies non-member of ASH