Biology subjects

Anandasabapathy, N.

Publications and source records attributed to Anandasabapathy, N..

4 recordsLinked to original sources

bioRxiv2026

Platelet-programmed circulating tumor cells signal to monocytes through a candidate CD40LG-ITGA5:ITGB1 myeloid checkpoint axis in breast cancer

Circulating tumor cells (CTCs) are key drivers of distant metastasis, while platelets facilitate this process by protecting them from immune surveillance. However, the detection of CTCs exhibiting platelet markers and their communication with monocytes has not been thoroughly investigated. This study seeks to identify the intercellular communication of CTCs that have acquired platelet traits by integrating single-cell RNA-seq data of 377 CTCs and 2,634 white blood cells. Trajectory analysis identified a subpopulation of CTCs with enhanced platelet-related functions, including platelet aggregation and resistance to NK cell-mediated cytotoxicity, termed Platelet-Programmed CTCs. The Dampened Weighted Least Squares method was implemented to estimate the platelet-programmed tumor cell proportion in 1,102 bulk RNA-seq samples from primary breast cancer tumors. A strong inverse association was found between platelet-programmed tumor cell proportion and overall survival (Cox-PH p-value =0.00419, HR=6 per 10% increase in proportion, 95% CI:1.76-20.7). However, this association did not differ significantly between early- and late-stage patients. Cell-cell communication analyses and molecular docking revealed the CD40LG-ITGA5:ITGB1 pair as a potential immune checkpoint candidate for monocytes in cancer (Hex score=-656.83; TNF-TNFR reference complex=-515). However, further experimental and clinical validation is required to translate these findings. In conclusion, these findings deepen our understanding of the immune evasion mechanisms of CTCs by acquiring platelet characteristics. This immune checkpoint axis offers a novel avenue for further experimental validation and future intervention.

cancer biology↗

bioRxiv2025

Epidermal Resident Memory T Cell Fitness Requires Antigen Encounter in the Skin

CD8+ tissue resident memory T cells (TRM) develop from effectors that seed peripheral tissues where they persist providing defense against subsequent challenges. TRM persistence requires autocrine TGF{beta} transactivated by integrins expressed on keratinocytes. TRM precursors that encounter antigen in the epidermis during development outcompete bystander TRM for TGF{beta} resulting in enhanced persistence. ScRNA-seq analysis of epidermal TRM revealed that local antigen experience in the skin resulted in an enhanced differentiation signature in comparison with bystanders. Upon recall, TRM displayed greater proliferation dictated by affinity of antigen experienced during epidermal development. Finally, local antigen experienced TRM differentially expressed TGF{beta}RIII, which increases avidity of the TGF{beta}RI/II receptor complex for TGF{beta}. Selective ablation of Tgfbr3 reduced local antigen experienced TRM capacity to persist, rendering them phenotypically like bystander TRM. Thus, antigen driven TCR signaling in the epidermis during TRM differentiation results in a lower TGF{beta} requirement for persistence and increased proliferative capacity that together enhance epidermal TRM fitness.

immunology↗

bioRxiv2022

Early life tolerance depends on a subset of specialized dendritic cells and is reinforced by the skin microbiota

Early life establishment of tolerance to commensal bacteria at barrier surfaces carries enduring implications for immune health but remains poorly understood. Here we show that this process is controlled by microbial interaction with a specialized subset of antigen presenting cells. More particularly, we identify CD301b+ type 2 conventional dendritic cells (DC) as a subset in neonatal skin specifically capable of uptake, presentation and generation of regulatory T cells (Tregs) to commensal antigens. In early life, CD301b+ DC2 are enriched for programs of phagocytosis and maturation, while also expressing tolerogenic markers. In both human and murine skin, these signatures were reinforced by microbial uptake. In contrast to their adult counterparts or other early life DC subsets, neonatal CD301b+ DC2 highly expressed the retinoic acid-producing enzyme, RALDH2, deletion of which limited commensal-specific Tregs. Thus, synergistic interactions between bacteria and a specialized DC subset critically support early life tolerance at the cutaneous interface.

immunology↗

bioRxiv2021

Type I interferon modulates Langerhans cell ADAM17 to promote photosensitivity in lupus

BackgroundThe autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure inflames skin. Beneficial effects of anifrolumab (anti-interferon /breceptor (anti-IFNAR)) on lupus skin disease support a pathogenic role for IFN-I, but mechanistic understanding is limited. We have shown that Langerhans cell (LC) dysfunction contributes to photosensitivity. Healthy LCs act via a disintegrin and metalloprotease 17 (ADAM17) to release epidermal growth factor receptor (EGFR) ligands that limit UVR-induced keratinocyte apoptosis and photosensitivity. However, LC ADAM17 activity is reduced in non-lesional lupus model skin, and data point to reduced LC-mediated protection in human lupus. Here, we asked about the role of the IFN-rich lupus skin environment in LC dysfunction and the implications of this regulation for photosensitivity. MethodsGene expression patterns in non-lesional skin from human lupus and multiple murine models were examined. We used MRL/lpr, B6.Sle1yaa, and imiquimod models of lupus in in vivo studies to assess the role of IFN-I in LC ADAM17 dysfunction and photosensitivity. ResultsWe show a shared IFN-rich environment in non-lesional skin across human and murine model systems, that IFN-I inhibits LC ADAM17 activity, and that anti-IFNAR in lupus models restores LC ADAM17 function and reduces photosensitivity in EGFR and LC ADAM17-dependent manners. Reactive oxygen species (ROS) can mediate ADAM17 activity, and we show reduced LC ROS expression in lupus models that is restored by anti-IFNAR. ConclusionsOur findings suggest that IFN-I promotes photosensitivity by causing LC ADAM17 dysfunction and that anifrolumab ameliorates lupus skin disease at least in part by restoring LC function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a mechanism of action for anifrolumab in lupus.

immunology↗