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The quantitative analysis of cell surface antigens has attracted increasing attention due to the antigenic variation recognition that can facilitate early diagnoses. This paper presents a novel methodology based on the optical “cell-tearing” and the especially proposed “dilution regulations” to detect variations in cell surface antigens. The cell attaches to the corresponding antibody-coated slide surface. Then, the cell-binding firmness between a single cell and the functionalized surface is assayed by optically tearing using gradually reduced laser powers incorporated with serial antibody dilutions. Groups B and B3 of red blood cells (RBCs) were selected as the experiment subject. The results indicate that a higher dilution called for lower power to tear off the cell binding. According to the proposed relative-quantitative analysis theory, antigenic variation can be intuitively estimated by comparing the maximum allowable dilution folds. The estimation result shows good consistency with the finding in the literature. This study suggests a novel methodology for examining the variation in cell surface antigens, expected to be widely capable with potential sensor applications not only in biochemistry and biophysics, but also in the micro-/nano- engineering field.

Background Uterine carcinosarcomas (UCS) are rare and aggressive gynecological tumors and the description of biomarkers that can help guide targeted treatments in this disease is a critical gap in current medical research. This study aims to measure the prevalence of trophoblast cell-surface antigen 2 (Trop-2) and folate receptor alpha (FRα) in UCS and evaluate their prognostic significance. Methods This retrospective analysis examined data from female patients diagnosed with UCS who underwent surgery followed by carboplatin and paclitaxel chemotherapy between January 2012 and December 2020. Tissue microarrays from 89 samples were assessed for Trop-2 and FRα expression by IHC. High positivity was defined as a score of ≥ 50% of tumor cells with strong staining intensity for Trop-2 and ≥ 75% with medium or strong staining intensity for FRα. Sociodemographic and clinical features were analyzed alongside progression-free survival (PFS) and overall survival (OS) outcomes. Results The mean age at diagnosis was 66.2 years (Standard Deviation, SD: 7) and the mean body mass index was 28.7 kg/m² (SD: 6.2). Non-white women accounted for 71.6% of cases. Heterologous subtype corresponded to 63.0% of cases, and lymphovascular invasion was observed in 59.2%. Complete resection (R0) was achieved in 66.3% of cases. High expression of Trop-2 and FRα was found in 49.4% and 17.4% of epithelial components, respectively, with no high positivity in sarcomatous components. Negative margins were more common in stage I/II disease ( p  = 0.001), and FRα overexpression correlated with Trop-2 overexpression ( p  = 0.007). On multivariate analysis, advanced stage ( p  = 0.015) and incomplete resection ( p  < 0.001) predicted shorter PFS, while both factors also independently worsened OS ( p  = 0.013 and p  = 0.001, respectively). Lymphadenectomy was associated with improved OS ( p  = 0.025). Conclusion Complete resection and advanced stage were suggested as prognostic factors in UCS. FRα and Trop-2 are increasingly recognized as therapeutic targets and their elevated expression levels in the epithelial component of UCS are promising, although not associated with prognosis in this cohort.

Efficient induction of target-specific antibodies can be elicited upon immunization with highly immunogenic virus-like particles (VLPs) decorated with desired membrane-anchored target antigens (Ags). However, for example, for diagnostic purposes, monoclonal antibodies (mAbs) are required to enable the histological examination of formaldehyde-fixed paraffin-embedded (FFPE) biopsy tissue samples. Aiming at the generation of FFPE-antigen-specific mAbs and as a proof of concept (POC), we first established a simplified protocol using only formaldehyde and 90 °C heat fixation (FF90) of cells expressing the target Ag nerve growth factor receptor (NGFR). The FF90 procedure was validated using flow cytometric analysis and two mAbs recognizing either the native and FFPE-Ag or exclusively the native Ag. C-terminally truncated NGFR (trNGFR)-displaying native and FF90-treated VLPs derived from HIV-1 did not reveal distinctive changes in particle morphology using transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis. Mice were subsequently repetitively immunized with trNGFR-decorated FF90-VLPs and hybridoma technology was used to establish mAb-producing cell clones. In multiple screening rounds, nine cell clones were identified producing mAbs distinctively recognizing epitopes in FF90- and FFPE-NGFR. This POC of a new methodology should foster the future generation of mAbs selectively targeting FFPE-fixed cell-surface Ags.

Chemoresistance and immune evasion constitute formidable obstacles in triple‐negative breast cancer (TNBC) therapy, exacerbated by the suboptimal pharmacokinetics and acquired resistance of antibody–drug conjugates (ADCs). Herein, we describe the engineering of antibody‐guided nanoparticles (NPs) co‐delivering the trophoblast cell‐surface antigen 2 (TROP2)‐targeting ADC sacituzumab govitecan (SG) with the mitochondria‐directed near‐infrared (NIR) photosensitizer AIE780. These AIE780–SG nanoconstructs exploit hRS7 antibody–mediated targeting to preferentially accumulate in TROP2‐overexpressing, SG‐resistant TNBC cells and patient‐derived organoid. Upon NIR irradiation, AIE780 induces a mitochondrial redox imbalance via localized reactive oxygen species generation, precipitating tumor‐selective immunogenic cell death (ICD) through membrane destabilization and oxidative necrosis. Concurrently, SG undergoes acid‐responsive cleavage to release SN‐38—a potent topoisomerase I inhibitor—and the hRS7 antibody fragment, which orchestrates natural killer (NK) cell recruitment and activation. In murine TNBC xenograft models, AIE780–SG NPs achieved synergistic chemophotodynamic tumor eradication, surmounting SG resistance and revitalizing antitumor immunity. This TROP2‐targeted, light‐sensitive theranostic platform offers a multimodal paradigm to potentiate ADC efficacy and reprogram the immunosuppressive TNBC microenvironment, heralding a novel strategy against SG‐resistant TNBC. A dual‐therapeutic nanoplatform combining targeted ADC delivery with photodynamic induction of ICD overcomes SG resistance in TNBC and amplifies NK cell‐mediated antitumor responses. Schematic of AIE780‐SG NPs for NIR FLI‐Guided Photo‐Enhanced Chemotherapy in Drug‐Resistant TNBC. AIE780‐SG (hRS7‐modified) targets TROP2 on TNBC cells to facilitate mitochondrial internalization. NIR illumination induces MICA/B release, recruiting and activating NK cells via MICA/B‐NKG2D and hRS7‐CD16 interactions, and enhancing secretion of cytotoxic molecules (GZMB, perforin, IFN‐γ). This nanomaterial precisely targets tumor cells, and its dual immune‐enhancing and direct DNA‐damaging mechanism boosts therapeutic efficacy against resistant TNBC.

Human trophoblast cell surface antigen 2 (TROP2) has been noted to serve an important role in the proliferation and migration of various types of human cancers. However, the potential role and the molecular mechanisms of TROP2 in osteosarcoma (OS) remain largely unclear. In the present study, high expression of TROP2 in human OS tissues and cell lines was observed. Overexpression of TROP2 promoted the proliferation and migration of OS cell lines, while TROP2 knockdown markedly decreased cell growth and migration. Furthermore, it was revealed that TROP2 overexpression significantly activated the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. Collectively, these results suggested that TROP2 may promote OS cell proliferation and migration via PI3K/AKT signaling and may serve as a novel treatment target for OS.

Osteosarcoma is a malignant tumor that produces neoplastic bone or osteoid osteoma. In human multicentric osteosarcoma (HMOS), a unique variant of human osteosarcoma (HOS), multiple bone lesions occur simultaneously or asynchronously before lung metastasis. HMOS is associated with an extremely poor prognosis, and effective treatment options are lacking. Using the proteins in our previously generated HMOS cell lines as antigens, we generated antibodies using a human antibody phage library. We obtained antibody clones recognizing 95 independent antigens and developed a fluorescence probe-based enzyme-linked immunosorbent assay (ELISA) technique capable of evaluating the reactivity of these antibodies by fluorescence intensity, allowing simple, rapid, and high-throughput selection of antibody clones. These results were highly correlated with those using flow cytometry. Subsequently, the HMOS cell lysate was incubated with the antibody, the antigen–antibody complex was recovered with magnetic beads, and the protein bands from electrophoresis were analyzed using liquid chromatography-mass spectrometry (LC/MS). CAVIN1/polymerase I transcript release factor was specifically detected in the HMOS cells. In conclusion, we found via a novel high-throughput screening method that CAVIN1/PTRF is an HMOS-specific cell membrane biomarker and an antigen capable of producing human antibodies. In the future, antibody–drug conjugate targeting of these specific proteins may be promising for clinical applications.

Prostate cancer is a heterogeneous disease composed of divergent molecular and histologic subtypes, including prostate adenocarcinoma (PrAd) and neuroendocrine prostate cancer (NEPC). While PrAd is the major histology in prostate cancer, NEPC can evolve from PrAd as a mechanism of treatment resistance that involves a transition from an epithelial to a neurosecretory cancer phenotype. Cell surface markers are often associated with specific cell lineages and differentiation states in normal development and cancer. Here, we show that PrAd and NEPC can be broadly discriminated by cell-surface profiles based on the analysis of prostate cancer gene expression datasets. To overcome a dependence on predictions of human cell-surface genes and an assumed correlation between mRNA levels and protein expression, we integrated transcriptomic and cell-surface proteomic data generated from a panel of prostate cancer cell lines to nominate cell-surface markers associated with these cancer subtypes. FXYD3 and CEACAM5 were validated as cell-surface antigens enriched in PrAd and NEPC, respectively. Given the lack of effective treatments for NEPC, CEACAM5 appeared to be a promising target for cell-based immunotherapy. As a proof of concept, engineered chimeric antigen receptor T cells targeting CEACAM5 induced antigen-specific cytotoxicity in NEPC cell lines. Our findings demonstrate that the surfaceomes of PrAd and NEPC reflect unique cancer differentiation states and broadly represent vulnerabilities amenable to therapeutic targeting.

Sebaceous carcinoma and sweat gland carcinoma (malignant tumors with apocrine and eccrine differentiation) are rare malignant skin adnexal tumors that differentiate toward sebaceous gland and eccrine and apocrine glands, respectively. Owing to the rarity of these carcinomas, standard treatments for advanced disease have not been established. Because the prognosis of patients with systemic metastasis is poor, a new treatment for these diseases is eagerly desired. Trophoblast cell surface antigen 2 (TROP2) and sacituzumab govitecan, an antibody–drug conjugate of TROP2, have attracted attention in the treatment of various solid tumors. In the current study, we immunohistochemically investigated TROP2 expression in 14 sebaceous carcinoma and 18 sweat gland carcinoma samples and found strong and relatively homogeneous TROP2 staining in both cancer types. The mean Histoscore, a semi-quantitative scoring ranging from 0 (negative) to 300, was 265.5 in sebaceous carcinoma and 260.0 in sweat gland carcinoma. These observations directly suggest that both sebaceous carcinoma and sweat gland carcinoma could be potentially treated with TROP2-targeted antibody–drug conjugates such as sacituzumab govitecan.

Background The chimeric antigen receptor (CAR)-T therapy has a limited therapeutic effect on solid tumors owing to the limited CAR-T cell infiltration into solid tumors and the inactivation of CAR-T cells by the immunosuppressive tumor microenvironment. Macrophage is an important component of the innate and adaptive immunity, and its unique phagocytic function has been explored to construct CAR macrophages (CAR-Ms) against solid tumors. This study aimed to investigate the therapeutic application of CAR-Ms in ovarian cancer. Methods In this study, we constructed novel CAR structures, which consisted of humanized anti-HER2 or CD47 scFv, CD8 hinge region and transmembrane domains, as well as the 4-1BB and CD3ζ intracellular domains. We examined the phagocytosis of HER2 CAR-M and CD47 CAR-M on ovarian cancer cells and the promotion of adaptive immunity. Two syngeneic tumor models were used to estimate the in vivo antitumor activity of HER2 CAR-M and CD47 CAR-M. Results We constructed CAR-Ms targeting HER2 and CD47 and verified their phagocytic ability to ovarian cancer cells in vivo and in vitro. The constructed CAR-Ms showed antigen-specific phagocytosis of ovarian cancer cells in vitro and could activate CD8 + cytotoxic T lymphocyte (CTL) to secrete various anti-tumor factors. For the in vivo model, mice with human-like immune systems were used. We found that CAR-Ms enhanced CD8 + T cell activation, affected tumor-associated macrophage (TAM) phenotype, and led to tumor regression. Conclusions We demonstrated the inhibition effect of our constructed novel HER2 CAR-M and CD47 CAR-M on target antigen-positive ovarian cancer in vitro and in vivo, and preliminarily verified that this inhibitory effect is due to phagocytosis, promotion of adaptive immunity and effect on tumor microenvironment.

Tisagenlecleucel therapy has shown promising efficacy for relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, relapses occur in 30–50% of patients. Determinants for CD19 pos versus CD19 neg relapses are poorly characterized. We report on 51 patients with R/R BCP-ALL (median age 17 years) infused with tisagenlecleucel after lymphodepletion. Complete remission rate at D28 was 96%. Prior blinatumomab increased the risk of early failure at D28. The 18-month cumulative incidence of relapse (CIR), event-free survival (EFS), and overall survival (OS) were 51%, 44%, and 74%, respectively, at a median follow-up of 15.5 months. Factors associated with a high tumor burden (occurrence of cytokine release syndrome) and prior blinatumomab were associated with an increased CIR, and a shorter EFS and OS. Pre-lymphodepletion high disease burden (MRD ≥ 10 –2 , SHR 10.4, p  = 0.03) and detectable MRD at D28 (SHR 7.2, p  = 0.006) correlated with an increased risk of CD19 neg relapse. Low disease burden (SHR 5.3, p  = 0.03) and loss of B-cell aplasia (BCA) (SHR 21.7, p  = 0.004) predicted an increased risk of CD19 pos relapses. These data highlight the impact of prior therapy on patient outcome. Finally, detectable MRD at D28 and loss of BCA both define patients at high risk of relapse for whom additional interventions are needed.