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.

Reprogramming of immunosuppressive tumor-associated macrophages (TAMs) presents an attractive therapeutic strategy in cancer. The aim of this study was to explore the role of macrophage CD5L protein in TAM activity and assess its potential as a therapeutic target.
Monoclonal antibodies (mAbs) against recombinant CD5L were raised by subcutaneous immunization of BALB/c mice. Peripheral blood monocytes were isolated from healthy donors and stimulated with IFN/LPS, IL4, IL10, and conditioned medium (CM) from different cancer cell lines in the presence of anti-CD5L mAb or controls. Subsequently, phenotypic markers, including CD5L, were quantified by flow cytometry, IF and RT-qPCR. Macrophage CD5L protein expression was studied in 55 human papillary lung adenocarcinoma (PAC) samples by IHC and IF. Anti-CD5L mAb and isotype control were administered intraperitoneally into a syngeneic Lewis Lung Carcinoma mouse model and tumor growth was measured. Tumor microenvironment (TME) changes were determined by flow cytometry, IHC, IF, Luminex, RNAseq and RT-qPCR.
Cancer cell lines CM induced an immunosuppressive phenotype (increase in CD163, CD206, MERTK, VEGF and CD5L) in cultured macrophages. Accordingly, high TAM expression of CD5L in PAC was associated with poor patient outcome (Log-rank (Mantel-Cox) test p = 0.02). We raised a new anti-CD5L mAb that blocked the immunosuppressive phenotype of macrophages in vitro. Its administration in vivo inhibited tumor progression of lung cancer by altering the intratumoral myeloid cell population profile and CD4+ T-cell exhaustion phenotype, thereby significantly modifying the TME and increasing the inflammatory milieu.
CD5L protein plays a key function in modulating the activity of macrophages and their interactions within the TME, which supports its role as a therapeutic target in cancer immunotherapy.
For a full list of funding bodies, please see the Acknowledgements.
Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.

T cell immunoglobulin and ITIM domain (TIGIT) is a recently identified T cell coinhibitory receptor. Studies have shown that TIGIT is expressed in colon adenocarcinoma, uterine corpus endometrioid carcinoma, breast carcinoma and kidney renal clear cell carcinoma. However, the role of the TIGIT/human poliovirus receptor (CD155) pathway in the pathogenesis of hepatocellular carcinoma (HCC) remains to be elucidated. In the present study, the expression of TIGIT and CD155 in HCC tissues and peripheral blood were determined, and correlations among TIGIT, CD155, TIGIT+ CD4+ T cells, TIGIT+ regulatory T (Treg) cells and α‑fetoprotein (AFP) were investigated in order to identify a potential target for diagnosing and treating HCC. Immunohistochemistry, reverse transcription‑quantitative PCR analysis and western blotting were used to examine the expression of TIGIT and CD155 in cancerous tissues and peripheral blood collected from patients with HCC. The frequency of TIGIT+ CD4+ T cells and TIGIT+ Treg cells and the concentration of inflammatory cytokines secreted by T cell subsets were analyzed by flow cytometry and a Merck Milliplex assay. Correlations between the frequency of TIGIT+ CD4+ T and TIGIT+ Treg cells and AFP were analyzed using Spearman's rank correlation test. With the degree of cancerous differentiation from high to low, the expression levels of TIGIT and CD155 were upregulated in the cancerous tissues from patients with HCC. TIGIT+ CD4+ T cell and TIGIT+ Treg cell frequencies were decreased in peripheral blood from postoperative patients with HCC. The increased expression of TIGIT was positively correlated with the level of AFP. These results indicate that co‑inhibitory receptor TIGIT may be involved in the pathogenesis of HCC and represent a novel target for the diagnosis and treatment of HCC.