AIMS
Small cell carcinoma of the bladder (SmCCB) is a rare and aggressive malignancy that remains poorly defined. Using the transcriptional taxonomy established for small cell lung carcinoma (SCLC), we aimed to stratify SmCCB by dominant transcription factors and assess associations between IHC-defined phenotype, neuroendocrine differentiation and therapeutic biomarker expression.
METHODS AND RESULTS
A retrospective multi-institutional cohort of 88 SmCCBs was assembled. Of these, 79 cases underwent immunohistochemical characterization for ASCL1, NEUROD1, POU2F3, YAP1 and HNF4α, along with classical neuroendocrine markers, therapeutic biomarkers and antibody-drug conjugate targets. NECTIN4 amplification was also assessed by fluorescence in situ hybridization (FISH). Six IHC-defined subgroups were identified: ASCL1-driven (41.8%), NEUROD1-driven (25.3%), POU2F3-driven (20.3%), YAP1-driven (6.3%), mixed (5.1%) and full-negative (1.3%). ASCL1-driven, NEUROD1-driven and mixed tumours were classified as High-NE, with diffuse NE marker expression, whereas POU2F3-driven, YAP1-driven and full-negative tumours were classified as Low-NE, with weak or absent expression. Overall membranous Nectin-4 expression was low or absent but significantly higher in Low-NE tumours (P < 0.001). NECTIN4 amplification occurred in 21.9% (16/73), comparable to that reported in non-neuroendocrine urothelial carcinoma. Conversely, DLL3 and SLFN11 were significantly overexpressed in High-NE tumours, while expression of the remaining targets was almost entirely absent.
CONCLUSIONS
SmCCB may be stratified into two IHC-defined phenotypic groups with distinctive neuroendocrine differentiation and therapeutic biomarker profiles. Taken together, low membranous Nectin-4 expression and preferential DLL3 and SLFN11 expression in High-NE tumours support further investigation of alternative therapeutic strategies.
N. Tenace, M. Colecchia, A. Hartmann et al.· Histopathology· 0 citations
Chimeric antigen receptor (CAR) T cell therapy in solid tumors is limited by the immunosuppressive tumor microenvironment (TME). Since we have identified T-bet as a strong anti-tumor candidate, we thought to explore new therapies against NSCLC by developing next-generation CAR T cells and patient-derived lung cancer organoids (PDOs) as a clinically relevant preclinical platform for evaluating CAR T cell antitumor efficacy.
To explore strategies that improve CAR T cell efficacy and persistence, we first characterized T cells in the lung tumor environment by flow cytometry. Next, we cultured PBMCs and purified CD3+ T cells from patients with NSCLC with IL-2 or IL-2+ IL-12 to assess the changes in T-bet expression in vitro. We thus engineered B7-H3 (CD276) directed CAR T cells co-expressing either IL-12 or the transcription factor T-bet (TBX21). Simultaneously, patient-derived organoids were established from lung cancer tissues to preserve tumor heterogeneity and architecture as a clinically relevant platform for CAR T cell antitumor efficacy evaluation.
Here we found low levels of Th1 T-bet + T cells in patients with NSCLC as compared to healthy controls. Moreover, in PBMCs under IL-2+ IL-12 stimulation, we found a significant expansion of CD3+CD4+ T-bet+ T cells. Preliminary data indicate that IL-12—armored CAR T cells exhibited the highest anti-tumor effect against the lung adenocarcinoma cell line A549, but raised concerns about systemic toxicity as confirmed in in vitro observations. In contrast, T-bet—modified CAR T cells displayed stronger CAR T cell survival and expansion associated with significant antitumor response.
This study leverages PDOs as a clinically relevant preclinical model to optimize CAR T design and supports T-bet as a promising axis for developing safer and more durable next generation CAR T therapies against NSCLC.
n/a
Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
Lin Li, D. Trufa, Bastian Zinkel et al.· Journal of Immunology· 0 citations
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