Niroshana Anandasabapathy

Figure: 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; TNFα–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.

The communication between skin and draining lymph nodes is crucial for immune responses to skin insults. Lymphatic vessels play key roles in this communication by transporting antigens from skin to lymph nodes, and mechanisms that compromise dermal lymphatic function can disrupt skin immunity. Here, we show that Langerhans cells (LCs), epidermis-derived antigen-presenting cells, promote dermal lymphatic expansion and phenotype acquisition during early life. This function was mediated by PlGF (placental growth factor) and VEGF-C (vascular endothelial growth factor C), and LCs selectively shaped the transcriptional profile of lymphatic endothelial cells. Compromise of this early-life LC-mediated lymphatic expansion reduced soluble antigen flow to draining lymph nodes and T cell responses in adulthood. Our data identify a tissue-based mechanism by which LCs regulate T cells remotely across time and space and raise the possibility that immune diseases in adulthood could reflect compromise of the LC-lymphatic axis in childhood.

The email address of the corresponding author has been updated

Immunogenicity and cross reactivity of CD8+ T transduced with specific AR H875Y TCRs

Single Cell TCRseq of donor 157 with AR H875Y 9-mer dextramer staining sorted T-cells

HLA-B*15:01 Binding Predictions for AR H875Y by NetMHCpan 8 to 14 flanking the mutation

Synthetic peptides used in this study

Specific AR H875Y T157.2 TCR reactivity in healthy donor PBMCs

Specific AR H875Y TCR cytotoxicity in healthy donor PBMCs