Repolarization of tumor infiltrating macrophages and increased survival in mouse primary CNS lymphomas after XPO1 and BTK inhibition

Abstract

Background Patients diagnosed with primary central nervous system lymphoma (PCNSL) often face dismal outcomes due to the limited availability of therapeutic options. PCNSL cells frequently have deregulated B-cell receptor (BCR) signaling, but clinical responses to its inhibition using ibrutinib have been brief. In this regard, blocking nuclear export by using selinexor, which covalently binds to XPO1, can also inhibit BCR signaling. Selinexor crosses the blood-brain barrier and was recently shown to have clinical activity in a patient with refractory diffuse large B-cell lymphoma in the CNS. We studied selinexor alone or in combination with ibrutinib in pre-clinical mouse models of PCNSL. Methods Orthotopic xenograft models were established by injecting lymphoma cells into the brain parenchyma of athymic mice. Tumor growth was monitored by bioluminescence. Malignant cells and macrophages were studied by immunohistochemistry and flow cytometry. Results Selinexor blocked tumor growth and prolonged survival in a bioluminescent mouse model, while its combination with ibrutinib further increased survival. CNS lymphoma in mice was infiltrated by tumor-promoting M2-like macrophages expressing PD-1 and SIRPα. Interestingly, treatment with selinexor and ibrutinib favored an anti-tumoral immune response by shifting polarization toward inflammatory M1-like and diminishing PD-1 and SIRPα expression in the remaining tumorpromoting M2-like macrophages. Conclusions These data highlight the pathogenic role of the innate immune microenvironment in PCNSL and provide preclinical evidence for the development of selinexor and ibrutinib as a new promising therapeutic option with cytotoxic and immunomodulatory potential.

Novel insights into the biomarkers and therapies for primary central nervous system lymphoma

“…This finding might provide a preclinical rationale for this two-novel-drug strategy for PCNSL. 100 Chidamide, an oral subtype-selective histone deacetylase inhibitor (HDACI), has been approved by China FDA for the treatment of r/r peripheral T-cell lymphoma (PTCL). 101 A recent study reported that chidamide could significantly upregulate the expression of CD20 on the surface of DLBCL cell lines; thus, it could synergize with rituximab to inhibit tumor growth of DLBCL.…”

Clinical Trials of the BTK Inhibitors Ibrutinib and Acalabrutinib in Human Diseases Beyond B Cell Malignancies

“…In particular, BTK is overexpressed in TAMs a n d M D S C s , w h i c h r e g u l a t e t u m o r p r o g r e s s i o n , immunosuppression and angiogenesis (71,84,85). Ibrutinib treatment, Btk deficiency or siRNA-mediated knockdown of BTK shifts macrophage polarization from tumor-promoting M2-like macrophages toward inflammatory M1-like and diminishes PD-1 and SIRPa expression on macrophages (24,77,86,87). Ibrutinib treatment also inhibits MDSC generation, induces MDSC differentiation to mature DCs, and impairs IDO expression and NO production in MDSCs, resulting in reduced MDSC-mediated immunosuppression and increased CD8 T cell proliferation, infiltration and effector function in the TME (71,80,84,88).…”

Recent Progress on Primary Central Nervous System Lymphoma—From Bench to Bedside

“…By using orthotopic xenograft models that were established by injecting lymphoma cells into the brain parenchyma of athymic mice, Jimeńez et al demonstrated that selinexor in combination with ibrutinib could effectively suppress tumor growth and prolong the survival of CNS lymphoma mice (35). Tumor cells in their brains were accompanied by tumorassociated macrophages (TAMs) and T cells.…”