Rodriguez-Peralto, J. L. | bioRxiv Science

bioRxiv2025

CD44v6 Drives Tumor Aggressiveness and Chemoresistance in Bladder Cancer

Bladder cancer is a fast-moving and recurrent malignancy where survival hinges on early detection and precise risk stratification. The search for robust biomarkers is urgent, and CD44v6 has emerged as a compelling candidate. In this study, we reveal that CD44v6 is not merely a marker but a driver of urothelial carcinoma aggressiveness. Through integrated clinical and functional analyses, we show that high CD44v6 expression is strongly associated with poor patient outcomes. Mechanistic investigations demonstrate that CD44v6 amplifies the proliferative, migratory, and invasive potential of bladder cancer cells, while conferring marked resistance to cisplatin. These findings position CD44v6 at the intersection of tumor progression and therapeutic failure, underscoring its value as both a prognostic biomarker and a promising therapeutic target. Targeting CD44v6 could pave the way for strategies that curb disease aggressiveness and overcome chemoresistance in bladder cancer.

cancer biology↗

bioRxiv2024

CD4+ tumor-infiltrating lymphocytes secreting T cell-engagers induce regression of autologous patient-derived non-small cell lung cancer xenografts

Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown remarkable results in melanoma, but only modest clinical benefit in other cancers, even after TIL have been genetically modified to improve their tumor homing, cytotoxic potential or overcoming cell exhaustion. The required ex vivo TIL expansion process may induce changes in the T cell clonal composition, which could likely compromise the tumor reactivity of TIL preparations and ultimately the success of TIL therapy. A promising approach based on the production of bispecific T cell engagers (TCE) by engineered T cells (STAb-T therapy) improves the efficacy of current T cell redirection strategies against tumor-associated antigens in hematological tumors. We studied the TCR{beta} repertoire in non-small cell lung cancer (NSCLC) tumors and in ex vivo expanded TIL from two unrelated patients. We generated TIL secreting anti-epidermal growth factor receptor (EGFR) x anti-CD3 TCE (TILSTAb) and tested their antitumor efficacy in vitro and in vivo using a NSCLC patient-derived xenograft (PDX) model in which tumor fragments and TIL from the same patient were transplanted into hIL-2 NOG mice. We confirmed that the standard TIL expansion protocol promotes the loss of tumor-dominant T cell clones and the overgrowth of virus-reactive TCR clonotypes that were marginally detectable in primary tumors. We demonstrated the antitumor activity of TILSTAb both in vitro and in vivo when administered intratumorally and systemically in an autologous immune-humanized PDX EGFR+ NSCLC mouse model, where tumor regression was mediated by TCE-redirected CD4+ TIL bearing non-tumor dominant clonotypes. SIGNIFICANCEEpithelial tumor-derived TIL can be engineered to secrete TCE capable of redirecting T cells bearing non-tumor-dominant clonotypes regardless of their phenotype, which could have broad applications in immunotherapy for solid tumors.

cancer biology↗