An analysis of the immune microenvironment in Waldenström macroglobulinemia (WM) revealed a regulatory T-cell (Treg) phenotype with a potential target involving CD40 and the CD40 ligand. Study results were reported in the journal Blood.

“Our findings show, to the best of our knowledge, for the first time, that patients with WM present with a Treg transcriptome and phenotype that may support WM tumor biology,” the study investigators wrote in their report. Prior research had shown possible roles for Tregs in tumor biology, but evidence for this in WM had been limited.

This study utilized transgenic mice modeling human-like lymphoplasmacytic lymphoma/WM. Compared with control mice, this lymphoplasmacytic lymphoma/WM murine model showed a higher level of Tregs.

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Based on this finding, the study investigators analyzed the transcriptomic profile of Tregs in patients with WM, which they compared with the Treg transcriptomic profile of age-matched healthy donors.

Profiling of the Treg transcriptomic profile in patients with WM revealed a messenger RNA pattern that was distinct from that of Tregs from healthy donors. Among other differences, the Treg transcriptomic profile in patients with WM was associated with enrichment in genes associated with signaling of interferon and nuclear factor kB-mediated tumor necrosis factor a, as well as genes associated with MAPK and PI3K/AKT.

Additionally, the transcriptomic pattern seen in patients with WM was associated with a Treg functional phenotype. WM cells showed greater Treg induction, expansion, and proliferation than B cells from healthy donors did, and WM Tregs appeared to have a greater capacity to suppress conventional T cells. WM cells with a CXCR4C1013G mutation demonstrated an even greater ability to influence Treg induction and growth than cells with wild-type CXCR4 did.

The investigators performed additional analyses of crosstalk between B cells and T cells that suggested the CD40/CD40-ligand axis was likely relevant to the interaction between WM cells and Tregs. Taken together, the investigators considered their results to support the notion that this crosstalk induces an immunosuppressive milieu.

When the CD40/CD40-ligand axis was inhibited, there also was inhibition of Tregs. Additionally, inhibition of the CD40/CD40-ligand axis was associated with reduced growth of WM cells.

The investigators considered the study’s findings to support the notion of Treg-mediated immunosuppression in WM, with regulation involving the CD40/CD40-ligand axis, which contributes to crosstalk between WM cells and Tregs. “Moreover, the results suggest how halting CD40/CD40-ligand interaction may represent a strategy to inhibit the Treg-mediated immunosuppressive scenario in WM, resulting in inhibition of WM cell proliferation,” the investigators noted in their report.

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of disclosures.


Sacco A, Desantis V, Celay J, et al. Targeting the immune microenvironment in Waldenström macroglobulinemia via halting the CD40/CD40-ligand axis. Blood. 2023;141(21):2615-2628. doi:10.1182/blood.2022019240