Search

Summary: Neuroblastoma exhibits two cellular phenotypes: therapy-sensitive adrenergic (ADRN) and therapy-resistant mesenchymal (MES). To understand treatment response, it is important to elucidate how these phenotypes impact the dynamics of cancer cell populations and whether they represent distinct cell types or dynamic cell states. Here, we use an integrated experimental and mathematical modeling approach. We experimentally measure the fractions of ADRN and MES phenotypes under baseline (untreated) conditions and under repeated treatment cycles. We develop evolutionary game theoretic models predicting how the populations would respond if ADRN and MES phenotypes (1) are distinct cell types or (2) represent dynamic cell states and fit these models to the experimental data. We find that, although cells may undergo an ADRN to MES phenotypic switch under treatment, the best-fit model sees ADRN and MES as distinct cell types. Differential proliferation and survival of these two cell types, and not cell-state switching, drive therapeutic response.

Summary: Nerve growth factor receptor (NGFR) is expressed by follicular dendritic cells (FDCs). However, the role of NGFR in the humoral response is not well defined. Here, we study the effect of Ngfr loss on lymph node organization and function, demonstrating that Ngfr depletion leads to spontaneous germinal center (GC) formation and an expansion of the GC B cell compartment. In accordance with this effect, stromal cells are altered in Ngfr−/− mice with a higher frequency of FDCs, characterized by CD21/35, MAdCAM-1, and VCAM-1 overexpression. GCs are located ectopically in Ngfr−/− mice, with lost polarization together with impaired high-affinity antibody production and an increase in circulating autoantibodies. We observe higher levels of autoantibodies in Bcl2 Tg/Ngfr−/− mice, concomitant with a higher incidence of autoimmunity and lower overall survival. Our work shows that NGFR is involved in maintaining GC structure and function, participating in GC activation, antibody production, and immune tolerance.

Schimke immuno-osseous dysplasia (SIOD) caused by mutations in SMARCAL1 is an ultra-rare disease characterized by specific facial features, skeletal dysplasia, and steroid-resistant nephrotic syndrome, which often leads to kidney failure and requires transplantation. Cellular (T-cell) deficiency, lymphopenia, and infections have been frequently reported, but whether they are due to T-cell-intrinsic defects in T-cell receptor (TCR) signaling associated with SMARCAL1 deficiency or to T-cell-extrinsic effects such as the impaired proliferation of hematopoietic precursors or T-cell-specific immunosuppression after renal transplantation remains unknown. We have explored the effects of SMARCAL1 deficiency on T-cell receptor signaling in primary and immortalized T cells from a 9-year-old SIOD patient under immunosuppression treatment when compared to healthy donors. Immortalized T cells recapitulated the SMARCAL1 deficiency of the patient, as judged by their impaired response to gamma irradiation. The results indicated that TCR-mediated signaling was normal in SIOD-derived immortalized T cells but strongly impaired in the primary T cells of the patient, although rescued with TCR-independent stimuli such as PMA + ionomycin, suggesting that SIOD-associated T-cell signaling is not intrinsically defective but rather the result of the impaired proliferation of hematopoietic precursors or of T-cell-specific immunosuppression. The lack of early thymic emigrants in our patients may support the former hypothesis.