Immune recognition and activation by the peptide-laden major histocompatibility complex-T cell receptor (TCR)-CD3 complex is essential for anti-tumor immunity. Tumors may escape immune surveillance by dissembling the complex. Here, we report that transferrin, which is overexpressed in patients with liver metastasis, disassociates TCR from the CD3 signaling apparatus by targeting the constant domain (CD) of T cell receptor α (TCRα), consequently suppresses T cell activation, and inhibits anti-metastatic and anti-tumor immunity. In mouse models of melanoma and lymphoma, transferrin overexpression exacerbates liver metastasis, while its knockdown, antibody, designed peptides, and CD mutation interfering with transferrin-TCRα interaction inhibit metastasis. This work reveals a novel strategy of tumor evasion of immune surveillance by blocking the coupling between TCRs and the CD3 signaling apparatus to suppress TCR activation. Given the conservation of CD and transferrin up-regulation in metastatic tumors, the strategy might be a common metastatic mechanism. Targeting transferrin-TCRα holds promise for anti-metastatic treatment.
Copyright © 2025 Ruomei Cheng et al.

The use of programmed death-1 (PD-1) inhibitors in the neoadjuvant setting for patients with resectable stage III NSCLC has revolutionized this field in recent years. However, there is still 40%-60% of patients do not benefit from this approach. The complex interactions between immune cell subtypes and tertiary lymphoid structures (TLSs) within the tumor microenvironment (TME) may influence prognosis and the response to immunochemotherapy. This study aims to assess the relationship between immune cells subtypes and TLSs to better understand their impact on immunotherapy response.
This study initially compared the tertiary lymphoid structures (TLSs) density among patients who underwent immunochemotherapy, chemotherapy and upfront surgery using 123 tumor samples from stage-matched patients. Multiplex immunohistochemistry (mIHC) was employed to analyze the spatial distribution of PD-L1+CD11c+ cells and PD1+CD8+ T cells within TLSs. Cytometry by time-of-flight (CyTOF) was used to assess immune cell dynamics in paired biopsy and resection specimens from six patients who underwent immunochemotherapy. Key immune cells were validated in newly collected samples using flow cytometry, mIHC, and in vitro CAR-T cells model.
Patients who underwent neoadjuvant chemotherapy or immunochemotherapy exhibited increased TLSs compared to those who opted for upfront surgery. The TLS area-to-tumor area ratio distinguished pCR+MPR and NR patients in the immunochemotherapy group. Spatial analysis revealed variations in the distance between PD-L1+CD11c+ cells and PD1+CD8+ T cells within TLSs in the immunochemotherapy group. CyTOF analysis revealed an increase in the frequency of key immune cells (CCR7+CD127+CD69+CD4+ and CD38+CD8+ cells) following combined therapy. Treatment responders exhibited an increase in CCR7+CD4+ T cells, whereas CD38+CD8+ T cells were associated with compromised treatment effectiveness.
Immunochemotherapy and chemotherapy increase TLSs and granzyme B+ CD8+ T cells in tumors. The TLS area-to-tumor ratio distinguishes responders from non-responders, with PD-L1+ dendritic cells near CD8+PD-1+ T cells linked to efficacy, suggesting that PD-1 inhibitors disrupt harmful interactions. Post-immunochemotherapy, CD8+ T cells increase, but CD38+CD8+ T cells show reduced functionality. These findings highlight the complex immune dynamics and their implications for NSCLC treatment.
Copyright © 2024 Yang, You, Wang, Chen, Tang, Chen, Zhong, Song, Long, Xiang, Zhao and Xia.

The efficacy of chemotherapy varies significantly among patients with gastric cancer (GC), and there is currently no effective strategy to predict chemotherapeutic outcomes. In this study, we successfully establish 57 GC patient-derived organoids (PDOs) from 73 patients with GC (78%). These organoids retain histological characteristics of their corresponding primary GC tissues. GC PDOs show varied responses to different chemotherapeutics. Through RNA sequencing, the upregulation of tumor suppression genes/pathways is identified in 5-fluorouracil (FU)- or oxaliplatin-sensitive organoids, whereas genes/pathways associated with proliferation and invasion are enriched in chemotherapy-resistant organoids. Gene expression biomarker panels, which could distinguish sensitive and resistant patients to 5-FU and oxaliplatin (area under the dose-response curve [AUC] >0.8), are identified. Moreover, the drug-response results in PDOs are validated in patient-derived organoids-based xenograft (PDOX) mice and are consistent with the actual clinical response in 91.7% (11/12) of patients with GC. Assessing chemosensitivity in PDOs can be utilized as a valuable tool for screening chemotherapeutic drugs in patients with GC.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

The DNA-binding peptide LL37 is a suspected autoantigen in psoriasis. It can be found in neutrophil extracellular traps (NETs) which have been suggested to play a role in the pathogenesis of the disease. Citrullination, the conversion of peptidyl-arginine into peptidyl-citrulline, can be implicated in the formation of NETs. We hypothesized that citrullination increases LL37 immunogenicity and that NETs are a source of LL37.
We aimed to characterize cytokine responses of B cells and T cells to native and citrullinated LL37 (citLL37) and determine the prevalence and composition of circulating NETs in patients with psoriasis and healthy blood donors (HDs).
Mononuclear cells (MNCs) and serum were isolated from 20 HDs and 20 patients with psoriasis. The MNCs were stimulated with native LL37 and citLL37 and the proportion of cytokine-positive B cells and T cells was determined by flow cytometry. Circulating antibodies against native LL37 and citLL37 as well as circulating NETs were measured by ELISA, as was the content of LL37, citLL37, and IgG in the NETs.
CitLL37, but not native LL37, induced IFN-γ-production by T cells and B cells from psoriasis patients, as well as IL-10-production by the patients' CD4+ T cells. Serum from 40% of patients and 55% of HDs contained circulating NETs, of which 63% and 27%, respectively, contained LL37. Only two patients had NETs containing citLL37 and IgG antibodies were found in NETs from three patients and one HD. Post-hoc analysis of the cytokines produced by B cells and T cells after stimulation with citLL37 revealed two clusters of patients consisting of 10 high-responders and 9 low-responders. The high-responders were those that had circulating NETs in combination with an earlier age of onset of the disease.
Citrullinated but not native LL37 elicits IFN-γ-responses by T cells and B cells from psoriasis patients, particularly those with circulating NETs and early disease onset, suggesting a role of citLL37 as an autoantigen in this subgroup of patients.
Copyright © 2023 Martín Monreal, Kvist-Hansen, Massarenti, Steffensen, Loft, Hansen, Ødum, Skov and Nielsen.

Autologous hematopoietic stem cell transplantation (autoHSCT) is a treatment option for hematological disorders and pediatric solid tumors. After an autoHSCT, natural killer (NK) cells are the first lymphocyte subset returning to normal levels. To uncover global changes during NK cell reconstitution after autoHSCT, we performed RNA-sequencing on NK cells before and after autoHSCT. Results showed profound changes in the gene expression profile of NK cells immediately after autoHSCT. Several biological processes including cell cycle, DNA replication and the mevalonate pathway were enriched. Significantly, we observed that following autoHSCT, NK cells acquired a decidual-like gene expression profile, including the expression of CD9. By using multiparametric flow cytometry, we confirmed the expansion of NK cells expressing CD9 immediately after autoHSCT, which exhibited higher granzyme B and perforin expression levels than CD9- NK cells. These results provide insights into the physiopathology of NK cells during their reconstitution after autoHSCT.
© 2022 The Author(s).