Biology subjects

Han, A. S.

Publications and source records attributed to Han, A. S..

3 recordsLinked to original sources

bioRxiv2025

Tyrosine kinase inhibitors affect sweet taste and dysregulate fate selection of specific taste cell subtypes via KIT inhibition.

Taste dysfunction, or dysgeusia, is a common side effect of many cancer drugs. Dysgeusia is often reported by patients treated with anti-angiogenic tyrosine kinase inhibitors (TKIs), which inhibit receptor tyrosine kinases (RTKs). However, the mechanisms by which TKIs cause dysgeusia are not understood, as the role of RTKs in adult taste homeostasis is unknown. Here, we find that treating adult mice with the TKI cabozantinib shifts the fate of differentiating functional taste cell subtypes within taste buds. Through behavioral assays, we find this cell fate shift leads to blunted responses to sweet in cabozantinib-treated mice. Finally, we show that inducible knockout of the RTK KIT, which is inhibited by cabozantinib, phenocopies taste cell fate shifts induced by TKI treatment. Our results establish KIT as a regulator of taste cell homeostasis and suggest that KIT inhibition may underlie TKI-induced dysgeusia in patients. SummaryKIT signaling blockade by tyrosine kinase inhibitors alters the fate of functional taste bud cell subtypes.

neuroscience↗

bioRxiv2024

Molecular characterization of the archaic HLA-B*73:01 allele reveals presentation of a unique peptidome and skewed engagement by KIR2DL2

HLA class I alleles of archaic origin may have been retained in modern humans because they provide immunity against diseases to which archaic humans had evolved resistance. According to this model, archaic introgressed alleles were somehow distinct from those that evolved in African populations. Here we show that HLA-B*73:01, a rare allotype with putative archaic origins, has a relatively rare peptide binding motif with an unusually long-tailed peptide length distribution. We also find that HLA-B*73:01 combines a restricted and unique peptidome with high-cell surface expression, characteristics that make it well-suited to combat one or a number of closely-related pathogens. Furthermore, a crystal structure of HLA-B*73:01 in complex with KIR2DL2 highlights differences from previously solved structures with HLA-C molecules. These molecular characteristics distinguish HLA-B*73:01 from other HLA class I alleles previously investigated and may have provided early modern human migrants that inherited this allele with a selective advantage as they colonized Europe and Asia.

biochemistry↗

bioRxiv2024

A CXCR4 partial agonist improves immunotherapy by targeting polymorphonuclear myeloid-derived suppressor cells and cancer-driven granulopoiesis

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that potently impair immunotherapy responses. The chemokine receptor CXCR4, a central regulator of hematopoiesis, represents an attractive PMN-MDSC target1. Here, we fused a secreted CXCR4 partial agonist TFF2 to mouse serum albumin (MSA) and demonstrated that TFF2-MSA peptide synergized with anti-PD-1 to induce tumor regression or eradication, inhibited distant metastases, and prolonged survival in multiple gastric cancer (GC) models. Using histidine decarboxylase (Hdc)-GFP transgenic mice to track PMN-MDSC in vivo, we found TFF2-MSA selectively reduced the immunosuppressive Hdc-GFP+ CXCR4hi tumor PMN-MDSCs while preserving proinflammatory neutrophils, thereby boosting CD8+ T cell-mediated anti-tumor response together with anti-PD-1. Furthermore, TFF2-MSA systemically reduced PMN-MDSCs and bone marrow granulopoiesis. In contrast, CXCR4 antagonism plus anti-PD-1 failed to provide a similar therapeutic benefit. In GC patients, expanded PMN-MDSCs containing a prominent CXCR4+LOX-1+ subset are inversely correlated with the TFF2 level and CD8+ T cells in circulation. Collectively, our studies introduce a strategy of using CXCR4 partial agonism to restore anti-PD-1 sensitivity in GC by targeting PMN-MDSCs and granulopoiesis.

cancer biology↗