Xupeng Yang

B lymphocytes are essential mediators of humoral immunity and play multiple roles in human cancer. To decode the functions of tumor-infiltrating B cells, we generated a B cell blueprint encompassing single-cell transcriptome, B cell-receptor repertoire, and chromatin accessibility data across 20 different cancer types (477 samples, 269 patients). B cells harbored extraordinary heterogeneity and comprised 15 subsets, which could be grouped into two independent developmental paths (extrafollicular versus germinal center). Tumor types grouped into the extrafollicular pathway were linked with worse clinical outcomes and resistance to immunotherapy. The dysfunctional extrafollicular program was associated with glutamine-derived metabolites through epigenetic-metabolic cross-talk, which promoted a T cell-driven immunosuppressive program. These data suggest an intratumor B cell balance between extrafollicular and germinal-center responses and suggest that humoral immunity could possibly be harnessed for B cell-targeting immunotherapy.

BACKGROUND: Dysfunction of skin steroidogenesis plays an important role in inflammatory skin diseases. We previously carried out an animal study which showed that icariin could inhibit the inflammation of atopic dermatitis by regulating the cutaneous hypothalamus-pituitary-adrenal axis (HPAA). AIM: To explore the immunomodulation of icariin on cutaneous HPAA by detecting the response to the inflammatory cytokines tumour necrosis factor-α/interferon-γ in HaCaT cells. METHODS: Cortisol level and the steroidogenesis-regulating enzymes CYP11A1 and CYP11B1 were measured to evaluate the level of skin steroidogenesis. In addition, the therapeutic effects of blocking CRH-R1 by the CRH-R1 inhibitor antalarmin and blocking the CRH-R1/2 signal pathway by the nonspecific CRH receptor antagonist astressin were observed. RESULTS: Unexpectedly, we found that icariin treatment blocked the secretion of the inflammatory cytokines and prevented initiation of steroidogenesis; however, prolonged treatment with icariin significantly increased steroidogenesis in HaCaT cells. The promoting effect of icariin on steroidogenesis was not dependent on the CRH-R1 pathway. CONCLUSION: Icariin has a regulatory effect on steroidogenesis in HaCaT cells, which may provide a promising therapeutic target for the treatment of inflammatory skin disorders.

Mutations in epidermal growth factor receptor (EGFR) are the key drivers of lung cancer initiation and recurrence. The cancer cells undergo transformation to a reversible drug-tolerant persister (DTP) state prior to the development of resistance against EGFR-tyrosine kinase inhibitors (TKIs). Two DTP lung cancer cells with different proliferative capacities are established and identified dipeptidyl peptidase 4 (DPP4) as a potential therapeutic target. The DTP cells primarily relied on oxidative phosphorylation, which is accompanied by the up-regulation of fatty acid metabolism. Mechanistically, DPP4 facilitates the uptake of fatty acids via carnitine palmitoyl transferase 1a (CPT1A, and enhances fatty acid oxidation. In addition, the DPP4-mitogen-activated protein kinase kinase (MEK)-Nuclear factor erythroid-2-related factor 2 (Nrf2) signaling pathway maintains mitochondrial function by activating the antioxidant pathway. The combination of osimertinib and sitagliptin, a DPP4 inhibitor, not only suppressed tumor progression but also reduced the number of residual tumor cells and minimal residual disease. Notably, this combination therapy significantly lowered recurrence rates and extended the survival of tumor-bearing mice compared to the monotherapies. The study provides new insights into the metabolic adaptations of DTP lung cancer cells in response to EGFR-TKIs, offering novel therapeutic strategies for targeting these persister cells.