Biology subjects

Hung, M. S.

Publications and source records attributed to Hung, M. S..

5 recordsLinked to original sources

bioRxiv2026

Fitness and immune-escape within germinal centers shape premalignant evolution toward lymphoma

Germinal centers (GCs) support physiological B-cell mutagenesis and are considered lymphoma-permissive; nevertheless, lymphoma development is uncommon. Human in situ follicular neoplasia (ISFN) captures this paradox: premalignant B-cells can persist within GCs for prolonged periods without progressing to overt lymphoma. We found that human ISFN, but not normal GCs, are infiltrated by CD8 T-cells, suggesting that premalignant GC B-cells are locally immune-surveilled. Using mouse models that separate early premalignant fitness from lymphoma-associated evolution, we show that fitness-enhanced premalignant GC B-cells expand transiently but are selectively eliminated by infiltrating cytotoxic CD8 T-cells, while normal GC B-cells are spared. By contrast, evolved premalignant GC B-cells retain their fitness but disable productive CD8 T-cell cytotoxic differentiation, allowing persistence and lymphoma-like transcriptional and genomic evolution. These findings establish GCs as active immune-surveillance sites and show that progression from premalignancy to lymphoma requires both enhanced GC fitness and escape from local immune control. Key findingsGCs undergo active immune-surveillance to detect premalignant B-cells. Premalignant GC B-cells trigger cytotoxic CD8 T-cell responses. Lymphoma-associated evolution enables immune-escape within GCs. Fitness and immune-escape drive evolution from premalignancy to lymphoma. BlurbGerminal centers are considered lymphoma-permissive; however, progression from premalignancy is uncommon. Using models of human in situ follicular neoplasia, Zhang et al. demonstrate that infiltrating CD8 T-cells actively eliminate premalignant GC B-cells. Co-occurrence of lymphoma-like alterations blocks this cytotoxic T-cell response, driving immune escape and lymphoma evolution.

cancer biology↗

bioRxiv2026

Relapse-founding cancer persister cells in follicular lymphoma

Follicular lymphoma (FL) is an incurable, prototypical relapse-remitting cancer, implying the existence of therapy-persistent cells that survive frontline treatment and seed disease recurrence1-3. However, these persister cells remain difficult to study directly in patients because immediate post-treatment sampling is ethically and practically challenging. Using a genetically defined mouse model that allows sampling of persistent cells immediately after frontline R-CHOP therapy, we prospectively isolate and functionally define relapse-founding cancer persister cells (CPC). The CPC is an IgM memory-like B-cell with high germinal center re-entry capacity. This state represents a discrete component of a heterogeneous residual pool indicating that residual disease is polytypic and that relapse potential may depend on which cells persist rather than on residual tumour burden alone. By integrating mouse CPC with human FL datasets, we show that an analogous transcriptional programme is detectable at diagnosis and is enriched in patients with inferior clinical outcome across independent cohorts4,5. These findings support the concept that relapse risk is linked to a conserved, genotype-agnostic CPC programme present before therapy. To explore therapeutic vulnerabilities, we developed a scalable in-vitro platform that models the CPC-like state and used it to identify sensitivity to histone deacetylase inhibition. Romidepsin and panobinostat killed CPC-like cells in-vitro, and decreased therapy-persistent cells after R-CHOP treatment in-vivo and in patient-derived organoids. Together, these data define a tractable CPC state in FL, with a validated clinical readout and an immediately testable therapeutic entry point, opening CPC-directed strategies for durable FL control.

cancer biology↗

bioRxiv2026

Booster vaccination improves the durability of antibody-secreting plasma cells

Booster vaccination can restore antibody titres and protection, but whether it improves long-term durability by expanding plasma cell (PC) numbers or also by shifting PC fate toward intrinsically longer-lived states remains unclear. Here we established longitudinal in vivo ground truth for PC persistence by combining PC-specific genetic timestamping, clonal tracking, and multi-timepoint single-cell profiling across spleen and bone marrow. We resolved PC longevity as a layered, non-binary architecture comprising short-, intermediate-, and long-lived programs, and showed that program identity is specified early in secondary lymphoid tissues and largely maintained as PCs populate bone marrow niches. Primary vaccine responses initiated from naive B-cells generated a prominent intermediate-lived wave, whereas memory B-cell recall during boosting redistributed output toward long-lived programs rather than recreating the intermediate-lived compartment characteristic of priming. Conserved longevity signatures projected onto early circulating PCs provide a cross-species framework to infer durability programs, supporting benchmarking of vaccine regimens by predicted persistence rather than peak titres. HighlightsO_LIGenetic timestamping resolves short-, intermediate-, and long-lived PC programs C_LIO_LILongevity programs are imprinted early and maintained from lymphoid organs to bone marrow C_LIO_LICross-species signatures stratify human blood and bone marrow PCs by persistence C_LIO_LIBoosting via MBC recall enriches long-lived PC and contracts the intermediate-lived tier C_LI

immunology↗

bioRxiv2026

Extrafollicular plasma cells disable dendritic cell-T-cell priming in tumor-draining lymph nodes

How plasma cells (PCs) shape anti-tumor immunity is unclear. We hypothesized that conflicting prognostic associations reflect differences in immune context and PC ontogeny. We identify extrafollicular (EF)-PCs as an antibody-independent checkpoint that aborts priming by disabling the cDC1[->]CD8+ T-cell axis in tumor-draining lymph nodes (td-LNs). EF-PCs blunt cDC1 activation and CCR7-guided repositioning into T-cell zones, precluding formation of TCF1 stem-like CD8 T-cells. Depleting EF-PCs in vivo restores cDC1 trafficking, expands the stem-like reservoir, increases intratumoral CD8 infiltration, and restrains tumor growth; benefit is lost with CD8 T-cell ablation. Neither serum transfer nor Fc{gamma} receptor blockade reverses tumor control, supporting a non-canonical, antibody-independent mechanism. Across independent triple-negative breast cancer cohorts, we find EF-PC hyperplasia in td-LNs and tumors; and within immune-cold cases, EF-PC burden stratifies poor prognosis and metastatic risk. A cross-species EF-PC signature maps to a conserved PC-state across cancer types that is linked to poor outcome and immune-checkpoint blockade resistance. EF-PCs thus relocate the dominant failure point to td-LNs and offer a tractable upstream target to convert immune-cold tumors into immune-responsive disease.

immunology↗

bioRxiv2025

Lactate Blocks Tertiary Lymphoid Structure Formation by Inhibiting B Cell Chemotaxis

Tertiary lymphoid structures (TLS) and B cell infiltration are strong predictors of immunotherapy success across cancers, including triple-negative breast cancer (TNBC). However, immune-cold TNBCs often lack both features. Here, we identify a tumor-intrinsic mechanism that actively suppresses B cell recruitment. Despite evidence of B cell responses in cancer-associated lymph nodes (cLNs), B cells fail to infiltrate TNBC tumors or form TLS. This exclusion is not simply due to chemokine deficiency as exogenous chemokine addition fails to restore B cell migration. Using fractionation and metabolic profiling, we identify lactate as a dominant tumor-secreted metabolite that directly impairs B cell chemotaxis by disrupting mitochondrial metabolism. In vivo, combining lactate inhibition with engineered chemokine secretion promotes cLN-derived B cell infiltration and enables TLS formation, particularly when coupled with CD40 stimulation. Transcriptomics analyses across several human cancer datasets strengthen the association between high glycolytic activity with poor B-cell infiltration in chemokine-rich tumors. Together, our findings reveal lactate as a key metabolic barrier to B cell trafficking and TLS induction, suggesting that metabolic reprogramming may provide an avenue to convert "immune-cold" tumors into TLS-rich, immunologically responsive microenvironments.

cancer biology↗