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431 Remodeling of the Immune Microenvironment By Oncogenic MYD88 Dictates Immunotherapy Responses across Indolent and Aggressive B-Cell Lymphomas

Program: Oral and Poster Abstracts
Type: Oral
Session: 622. Lymphomas: Translational – Non-Genetic: Elucidating Biomarkers and Mechanisms of Therapy in Lymphoma
Hematology Disease Topics & Pathways:
Research, Biological therapies, Antibody Therapy, Translational Research, Lymphomas, non-Hodgkin lymphoma, Non-Biological therapies, B Cell lymphoma, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Combination therapy, genomics, Diseases, indolent lymphoma, immune mechanism, aggressive lymphoma, Therapies, immunology, Lymphoid Malignancies, Infusion, computational biology, Biological Processes, Technology and Procedures, profiling, pathogenesis, Pathology
Sunday, December 10, 2023: 10:30 AM

Jon Celay, PhD1*, Miriam Recalde, PhD2*, María Victoria Revuelta, PhD3*, Marta Larrayoz, PhD2*, Sara Rodriguez, PhD2*, Maria J Garcia-Barchino, PhD2*, Jennifer R. Chapman-Fredricks, MD4*, Teresa Lozano, PhD5*, Juan J Lasarte, PhD5*, Ming Q. Du, MD6*, Izidore S. Lossos, MD7, Sergio Roa, PhD8*, Aldo Roccaro, MD, PhD9, Miguel Canales10*, Felipe Prosper, MD, PhD11, Bruno Paiva11*, Leandro Cerchietti, MD12 and Jose A. Martinez-Climent, MD/PhD2

1Hematology and Oncology Program, Centre for Applied Medical Research (CIMA), Instituto de Investigaciones Sanitarias de Navarra (IdiSNA), Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, Navarra, Spain
2Center for Applied Medical Research, Clinica University of Navarra Cancer Center, University of Navarra, Pamplona, Spain
3Weill Cornell Medicine, New York, NY
4Department of Pathology and Laboratory Medicine, University of Miami, Miami, FL
5Immunology and Immunotherapy Program. Cima Universidad de Navarra. IdiSNA., Pamplona, Spain
6Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom
7Sylvester Comprehensive Cancer Center, Division of Hematology, University of Miami School of Medicine, Miami, FL
8Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain
9Clinical Trial Center, Translational Research and Phase I Unit, ASST Spedali Civili di Brescia, Brescia, BS, Italy
10Department of Hematology, Clínica Universidad de Navarra; Hematology and Oncology Program, Center for Applied Medical Research (CIMA); Instituto de Investigaciones Sanitarias de Navarra (IdiSNA), Pamplona, Spain
11Cancer Center Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), IDISNA, CIBER-ONC number CB16/12/00369 and CB16/12/00489, Pamplona, Spain
12Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medical College, New York, NY

The MYD88L265P mutation is detected in a variety of lymphoma subtypes, ranging from indolent MALT or lymphoplasmacytic lymphoma (LPL) to aggressive DLBCL with activated B-cell (ABC) phenotype. Whether oncogenic MYD88L265P constitutes a common founder mutation and how it drives lymphomas with different clinical, histopathological, and immunological characteristics, remains unknown. To address this fundamental question, we screened mice genetically engineered to express an orthologous MYD88L252P mutation crossed with animals carrying secondary genetic lesions common in MYD88L265P lymphomas, triggered at two B-cell differentiation stages. Several mouse strains developed indolent or aggressive lymphomas depending on the cell of origin and the secondary genetic lesion. In two of the models, human-like MALT or LPL were progressively driven by mutant MYD88 activated from immature pre-B lymphocytes with either constitutive BCR signaling or BCL2 expression. High-throughput cellular and molecular characterization of the tumor immune microenvironment (TME) by single-cell RNA sequencing coupled with BCR/TCRseq revealed bi-directional B-cell interactions with CD4+ Tfh and Th1 cells from early disease state, promoting survival of B-cell clones through CD40L:CD40 signaling. During progression, IL10-secreting regulatory T (Treg) cells were recruited into the tumor niche through a Ccl5-Cxcr3 axis to suppress CD8+ T-cell cytotoxicity. In patients with MYD88L265P LPL characterized at progressive disease states, CD40:CD40L interaction between tumor and immune cells took place early while Tregs accumulated at late stage. In the LPL model and in human MYD88L265P-LPL cells, CD40 signaling decreased effects of standard-of-care drugs including BTK inhibitors. Accordingly, anti-CD40 therapy disrupted B/T-cell interactions and increased ibrutinib activity. In conclusion, oncogenic MYD88 triggered at early B-cell stages promotes indolent lymphomas that are sustained by CD40 signaling, which restricts therapy responses that can be restored upon CD40 blockade.

When MYD88L265P was activated in mature germinal-center B cells together with either Prdm1 or Trp53 deletion, mice developed extranodal ABC-DLBCL (MCD/C5 genomic class). IHC, flow cytometry and single-cell RNAseq revealed that DLBCL with Prdm1 loss showed morphologically heterogeneous B cells with abundant immune and T cells with activated/exhausted phenotypes, which recapitulated the inflammatory/immunosuppressive TME category in DLBCL patients (IN-LME, Kotlov- Cancer-Discovery-2021). In contrast, DLBCL with Tp53 deletion exhibited monotonous B-cell infiltrates with high proliferation index and a TME with depletion of T cells with effector/memory phenotypes and CD4+CD25+Foxp3+ Tregs, consistent with the immune depleted TME category (DP-LME). Analysis of 1,039 DLBCL patients demonstrated that majority of MCD cases with MYD88L265P showed either an IN-LME (43%) or DP-LME (44%). Consistent with the models, ABC-DLBCL patients with MYD88L265P and TP53 loss/mutation exhibited highly proliferative disease with a DP-LME, while ABC-DLBCLs with MYD88L265P but without TP53 abnormalities showed an IN-LME. Notably, the number of infiltrating CD4+ T cells correlated with TP53 activity score (PROGeNY) across MCD-DLBCLs. Overall, the presence or absence of TP53 alterations in MYD88L265P ABC-DLBCL induces TME characterized as DP-LME or IN-LME, respectively. Since DP-LME carries poor response to immune-chemotherapy (Kotlov-Cancer-Discovery-2021), we tested anti-CD19 CAR T-cells in the models. While CAR T-cells were initially effective in the two DLBCL models, progression occurred earlier in DLBCL with DP-LME than in IN-LME, which remained in remission 100 days after cell infusion. Responses correlated with persistence of circulating CD4+ CAR T cells. These data highlight that a TP53-driven DP-LME may limit immunotherapy activity in DLBCL, providing a scientific explanation to the poor outcome of DLBCL patients with TP53 alterations to CD19-directed CAR T cells (Shouval-JCO-2021). Collectively, our study defines the cellular origins and the stepwise genetic alterations of indolent and aggressive lymphomas with MYD88L265P, dissects distinct immunological paths underlying progression driven by oncogenic MYD88, and builds proof-of-concept for advancing precision immunotherapy in B-cell lymphomas.

Disclosures: Lossos: LRF: Membership on an entity's Board of Directors or advisory committees; NCI: Research Funding; Adaptive: Honoraria; University of Miami: Current Employment; NCI: Research Funding; BeiGene: Consultancy. Roa: Roche-Genentech: Research Funding. Roccaro: Italian Foundation for Cancer Research; Transcan2-ERANET; AstraZeneca: Research Funding; Amgen, Celgene, Janssen. Takeda: Consultancy. Canales: Beigene: Consultancy; BMS: Consultancy; Incyte: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Kite: Consultancy; Kyowa: Consultancy; Lilly: Consultancy; Roche: Consultancy; Takeda: Consultancy; Incyte: Speakers Bureau; Janssen: Speakers Bureau; Kite: Speakers Bureau; Kyowa: Speakers Bureau; Roche: Speakers Bureau; Takeda: Speakers Bureau. Paiva: Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; EngMab: Research Funding; Roche Glycart AG: Honoraria, Research Funding; Adaptive: Honoraria; Amgen: Honoraria; Gilead: Honoraria; Oncopeptides: Honoraria. Martinez-Climent: Roche/Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Janssen: Research Funding; Astra Zeneca: Research Funding; Palleon Pharnaceuticals: Research Funding; Regeneron: Research Funding; Priothera: Research Funding.

*signifies non-member of ASH