Abstract 7234: Unveiling the role of B7H3 in driving the tumor immune microenvironment and progression of small cell lung cancer
Authors: Mahek Fatima, Parvez Khan, Md Arafat Khan, Asad Ur Rehman, Laiba Anwar, Aatiya Ahmad, Jaewon Lee, Imayavaramban Lakshmanan, Anish Thomas, Dinesh Pradhan, Apar K. Ganti, Brad St Croix, Surinder K. Batra, Mohd Wasim Nasser
Journal: Cancer Research (2025)

Abstract Lung cancer is the leading cause of cancer-related deaths globally, with small cell lung cancer (SCLC) representing a highly aggressive subtype. The prognosis for SCLC remains dire due to early metastasis, chemoresistance, high recurrence rates, and limited therapeutic options. Despite the approval of some immunotherapeutic drugs for SCLC, their efficacy is restricted to a small subset of patients. This limited success is attributed to low expression of PD-L1 and the immune-cold tumor microenvironment in SCLC, underscoring the urgent need for new therapeutic targets. Bioinformatic analysis of SCLC datasets, focusing on immune checkpoint regulators, identified B7H3 (CD276) as a promising candidate upregulated in SCLC. This finding was confirmed in SCLC cell lines and human tissue samples. B7H3 is a cell surface protein overexpressed in multiple tumor types, functioning as both an immune modulator and an oncogenic driver. However, its role in SCLC tumorigenesis remains unclear. To investigate the functional involvement of B7H3 in SCLC, we employed CRISPR-Cas9 to knock out the B7H3 gene in SCLC cell lines. B7H3 knockout significantly reduced transwell migration and wound-healing abilities in SCLC cells. When co-cultured with T-cells, B7H3-proficient SCLC cells suppressed T cell activation, unlike their B7H3-deficient counterparts. To therapeutically target B7H3, we used the antibody-drug conjugate (ADC) m276-SL-PBD in the spontaneous SCLC mouse model RPM (Adeno-CGRP-Cre; Rb1flox/flox; TP53flox/flox; LSL-MycT58A) which significantly reduced tumor burden, metastasis, angiogenesis, and increased T cell infiltration. To further elucidate the role of B7H3 in SCLC progression, we generated a novel spontaneous mouse model, RPMC (Adeno-CGRP-Cre; Rb1flox/flox; TP53flox/flox; LSL-MycT58A; Cd276fl/fl). These mice exhibited a marked decrease in tumor burden, tumor-associated angiogenesis, and metastasis, with a significantly increased T-cell infiltration compared to controls. Transcriptomic analysis of B7H3-proficient/-deficient cells revealed NFIB among the top 50 downregulated genes following B7H3 deletion. NFIB, a key driver of SCLC metastasis, was significantly reduced in B7H3-deficient human and syngeneic (RPMC) cell lines. Metastatic tissues from RPMC mice also showed lower NFIB expression compared to the RPM model. In conclusion, this study highlights the critical role of B7H3 as well as modulation of NFIB expression in regulating SCLC progression. Our findings establish B7H3 as a promising therapeutic target and demonstrate the potential role of CD276 ADCs in overcoming the limitations of current treatments of SCLC. By advancing our understanding of B7H3’s role in promoting tumor growth, this study paves the way for designing more effective therapeutic strategies to combat SCLC. Citation Format: Mahek Fatima, Parvez Khan, Md Arafat Khan, Asad Ur Rehman, Laiba Anwar, Aatiya Ahmad, Jaewon Lee, Imayavaramban Lakshmanan, Anish Thomas, Dinesh Pradhan, Apar K. Ganti, Brad St Croix, Surinder K. Batra, Mohd Wasim Nasser. Unveiling the role of B7H3 in driving the tumor immune microenvironment and progression of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7234.