Primary Central Nervous System (CNS) Lymphoma B Cell Receptors Recognize CNS Proteins

Abstract

Primary lymphoma of the CNS (PCNSL) is a diffuse large B cell lymphoma confined to the CNS. To elucidate its peculiar organ tropism, we generated recombinant Abs (recAbs) identical to the BCR of 23 PCNSLs from immunocompetent patients. Although none of the recAbs showed self-reactivity upon testing with common autoantigens, they recognized 1547 proteins present on a large-scale protein microarray, indicating polyreactivity. Interestingly, proteins (GRINL1A, centaurin-α, BAIAP2) recognized by the recAbs are physiologically expressed by CNS neurons. Furthermore, 87% (20/23) of the recAbs, including all Abs derived from IGHV4-34 using PCNSL, recognized galectin-3, which was upregulated on microglia/macrophages, astrocytes, and cerebral endothelial cells upon CNS invasion by PCNSL. Thus, PCNSL Ig may recognize CNS proteins as self-Ags. Their interaction may contribute to BCR signaling with sustained NF-κB activation and, ultimately, may foster tumor cell proliferation and survival. These data may also explain, at least in part, the affinity of PCNSL cells for the CNS.

Comment on “Primary Central Nervous System (CNS) Lymphoma B Cell Receptors Recognize CNS Proteins”

“…In contrast, control BCRs from mantle cell lymphoma showed no brain reactivity, clearly arguing in favor of disease specificity. These findings strengthen the data presented by Montesinos-Rongen et al (4) and complement it at a structural level. Moreover, (Fig.…”

Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma

“…MYD88 mutations, for example, have been linked to ibrutinib sensitivity in Waldenström Macroglobulinemia (16) and are significantly more common in PCNSL than in DLBCL outside the CNS. Alternatively, the brain microenvironment might augment BTK dependence of lymphoma cells through chronic antigen presentation and BCR activation (43,44), perhaps explaining the observed greater than expected response rate to ibrutinib in SCNSL patients. Further studies are needed to determine how genetic and tumor microenvironmental factors, alone or in combination, create intrinsic BTK dependence in different B cell malignancies (4,18).…”

Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling

“…[12][13][14] in chronic lymphocytic leukemia (CLL), 15 marginal zone lymphoma, 16 FL, [17][18][19] and DLBCL. 20,21 In other lymphoma types, BCR signaling nodes are frequently altered by recurrent mutations. In the activated B-cell (ABC) subtype of DLBCL, mutations of CD79B, CARD11, and the negative regulator of NF-kB TNFAIP3/A20 occur in about 21%, 11%, and 30% of cases, respectively.…”