Our research group delves into the fundamental molecular and cellular processes underlying the development of protective antibodies and the establishment of enduring immunity. Employing a combination of mouse models and human-derived tissues, along with advanced imaging techniques and next-generation genomics, we unveil the regulatory mechanisms governing antibody-mediated immunity in the context of vaccination, pathogen invasion, and cancer.
Nathan N., Paparoditis P., Sarusi-Portuguez A., Stoler-Barak L., Horn H. M., Milo I., Mazor R. D., Levy-Barda A., Yanichkin N., Borcherding N., Blecher-Gonen R., Ronen R., Nachman I. B., Goliand I., Fellus-Alyagor L., Salame T. M., Sagi I., Siloni G. H., Gross M., Tenenbaum A., Kent I., Keren L., Raban O., Eitan R. & Shulman Z.
(2026)
Immunity.
59,
6,
p. 1743-1757.e10
The presence of B cells within high-grade serous ovarian cancer (HGSOC) tumors associates with favorable prognoses. We examined the contribution of tumor-draining lymph nodes (TDLNs) to the anti-tumor B cell response. Patient-derived TDLNs were largely devoid of active germinal center (GC) structures, plasma cells (PCs), and T follicular helper cells and were instead dominated by quiescent memory B cells (MBCs) that expressed mutated, class-switched antibodies reactive to ovarian tumor cells. GC B cells and PCs largely resided within the tumor, whereas classical class-switched MBCs were present both in the tumor and in matched TDLN samples. MBCs located in the TDLNs were clonally related to MBCs and PCs within the tumor. Increased frequencies of DC-SIGN\u207a macrophages in TDLNs were correlated with reduced presence of GC B cells, suggesting a regulatory role. Thus, in HGSOC, TDLNs fail to sustain active GC responses, serving instead as reservoirs of tumor-reactive memory B cells that contribute to the intra-tumoral B cell response.
In this issue of Cancer Cell, Bashir et al. show that stress-induced corticosterone suppresses germinal center B cell responses and impairs anti-tumor immunity. Their study identifies gut microbiota-derived phage DNA as a key trigger of TLR9 activation and corticosterone secretion by cancer-associated fibroblasts, revealing an intricate bacteria-driven immune-suppression mechanism.
Liu J., Stoler-Barak L. & Shulman Z.
(2026)
Journal of Experimental Medicine.
223,
4,
e20251901.
Antibody-mediated immune responses in mucosal tissues are critical for defending against pathogens while maintaining homeostasis with commensals. Nasal vaccination aims to induce local protection in the upper airway mucosa. Although B cell-driven immunity is well characterized in gut-associated lymphoid tissues such as Peyer's patches and mesenteric LNs, much less is known about analogous processes in the upper airways. Here, we show that B cell receptor (BCR) affinity and CCR6 regulate germinal center (GC) seeding and class-switch recombination (CSR) to IgA in nasal-associated lymphoid tissue (NALT) following nasal vaccination. B cells bearing low-affinity BCRs failed to upregulate CCR6 and did not support T follicular helper cell differentiation or seed GCs in the NALT. CCR6-deficient B cells were unable to migrate to the NALT subepithelial dome or undergo IgA CSR and seed GC effectively in response to nasal vaccination or commensal bacteria signals. Thus, effective targeting of B cell clones to induce CCR6 expression is essential for nasal vaccine design.
