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1587 Autoimmunity Checkpoints As Therapeutic Targets in B-Cell Malignancies

Program: Oral and Poster Abstracts
Session: 622. Lymphoma Biology—Non-Genetic Studies: Poster I
Hematology Disease Topics & Pathways:
Biological, Diseases, Leukemia, Therapies, Biological Processes, B-Cell Lymphoma, immunotherapy, Lymphoid Malignancies, signal transduction
Saturday, December 1, 2018, 6:15 PM-8:15 PM
Hall GH (San Diego Convention Center)

Zhengshan Chen, MD-PhD1* and Markus Muschen, MD1,2,3

1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, CA
2Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia CA, Monrovia, CA
3Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia CA, San Francisco, CA

Concept. Targeted therapy of cancer typically focuses on inhibitors (e.g. tyrosine kinase inhibitors) that suppress oncogenic signaling below a minimum threshold required for survival and proliferation of cancer cells. Acute lymphoblastic leukemia (ALL) and B cell lymphomas originate from various stages of development of B cells, which unlike other cell types are under intense selective pressure. The vast majority of newly generated B cells are autoreactive and die by negative selection at autoimmunity checkpoints (AIC). Owing to ubiquitous encounter of self-antigen, autoreactive B cells are eliminated by overwhelming signaling strength of their autoreactive B cell antigen receptor (BCR). A series of recent findings suggests that, despite malignant transformation, AIC are fully functional in B cell malignancies. We propose that targeted engagement of AIC represents a previously unrecognized therapeutic opportunity to overcome conventional mechanisms of drug-resistance in pre-B ALL and other B cell malignancies.

Results: Oncogenic drivers in B- cell malignancies function as mimics of B-cell receptor (BCR) signaling. Oncogenic activation of BCR-signaling represents the functional equivalent of positive selection during normal lymphocyte development. Addiction to survival and proliferation signals (or the equivalent of positive selection) is a common feature in many types of cancer. However, B-cell malignancies are unique in that they are also subject to an active negative selection process. B-cells expressing autoreactive BCRs or antibodies can cause systemic autoimmunity. As a safeguard against autoimmune diseases, lymphocyte development evolved autoimmunity checkpoints (AIC) to eliminate autoreactive clones. Owing to negative selection of autoreactive B-cells through AIC activation, lymphoid cells fundamentally differ in their signaling requirements from other cell types. Recent studies from our group showed that despite malignant transformation, B-cell leukemia and lymphoma cells are fully sensitive to negative selection and AIC-activation resulting (Chen et al., Nature 2015; Shojaee et al., Nature Med 2016; Chan et al., Nature 2017; Xiao et al., Cell 2018).

AIC-activation in various lymphoid malignancies is achievable by pharmacological hyperactivation of BCR-signaling above a maximum threshold (see Schematic below). Unlike other types of cancer, B-cell malignancies are uniquely susceptible to clonal deletion induced by hyperactive signaling from an autoreactive BCR. Hence, targeted AIC-activation can be leveraged for eradication of drug-resistant leukemia and lymphoma clones. Here, we propose a novel strategy to overcome drug-resistance in B-lymphoid malignancies based on targeted activation of autoimmunity checkpoints (AIC) for removal of autoreactive B-lymphocytes.

We have recently discovered that targeted hyperactivation of SYK, PI3K and ERK in B cell malignancies represents the functional equivalent of an autoimmunity checkpoint (AIC) for elimination of autoreactive clones among normal B cells. B cell tumors are uniquely vulnerable to AIC activation, suggesting that targeted activation of this checkpoint represents a novel strategy to induce cell death in otherwise drug-resistant B cell malignancies.

Conclusion: Normal B-cells are positively selected for BCR signaling of intermediate strength (moderate activation of SYK, PI3K and ERK). In the absence of a functional BCR, SYK, PI3K and ERK activity fall below a minimum threshold, resulting in death by neglect. Hyperactivation above maximum thresholds (e.g. autoreactive BCR) triggers negative selection and cell death via AIC-activation. Targeted therapy of cancer typically focuses on agents that suppress oncogenic signaling below a minimum threshold. Our results support a novel strategy to overcome drug-resistance in B-cell malignancies based on targeted activation of autoimmunity checkpoints (AIC) for removal of autoreactive cells.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH