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Antitumor effects of anti-CD4-depleting antibody in lung fibrosis through CD8+ T cell activation and regulatory T cell inhibition in mice

ABSTRACT: Background Lung cancer (LC) as a complication worsens the prognosis of patients with idiopathic pulmonary fibrosis (IPF); however, the underlying mechanisms are not fully understood. This study aimed to investigate the immunological characteristics of IPF-LC. Methods We created a murine IPF-LC complication model by intravenous administration of Lewis lung carcinoma cells into bleomycin-induced pulmonary fibrosis model mice. We administered anti-CD4 monoclonal antibody (mAb) to the mice and evaluated the effects on tumor growth, T-cell phenotype in the lungs and lymph nodes, and survival rate. T-cell phenotype was analyzed by flow cytometry and survival analysis was performed using the Kaplan-Meier method. Results Tumor number and size were both significantly increased in this model. CD8+ T cells were significantly decreased, while regulatory T cells (Tregs) were significantly increased in the lungs and lymph nodes. Anti-CD4 mAb treatment significantly increased the number and antitumor gene expression of CD8+ T cells, suppressed tumor growth in fibrotic lungs, reduced the number of Tregs, and improved survival. Conclusions These results indicate that anti-CD4 mAb treatment inhibits tumor growth by enhancing the number and antitumor activity of CD8+ T cells in IPF-LC mice. Anti-CD4 mAb may thus be a promising clinical therapeutic option in patients with IPF-LC.

ORGANISM(S): Mus musculus

PROVIDER: GSE315687 | GEO | 2026/01/08

REPOSITORIES: GEO

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Project description:Using both global and conditional knockout mice, we demonstrated that the transcription factor Basic Helix-Loop-Helix Family Member E40 (BHLHE40/DEC1) is required in T cells for rejection of mouse syngeneic tumors upon immune checkpoint therapy (ICT) with anti-PD-1 or anti-CTLA-4 monoclonal antibody (mAb) treatment. Using single cell RNA sequencing (scRNAseq) we profiled intratumoral CD45+ cells from syngeneic mouse sarcomas that (a) grow progressively with control treatment in either Bhlhe40+/+ or Bhlhe40-/- tumor-bearing mice, (b) reject following anti-PD-1 or anti-CTLA-4 ICT in Bhlhe40+/+ tumor-bearing mice, or (c) grow progressively following anti-PD-1 or anti-CTLA-4 in Bhlhe40-/- mice. We performed two separate scRNAseq experiments with the same conditions but harvested tumors on either day 9 post-tumor transplant or day 11 post-tumor transplant. The groups were as follows: (1) Control mAb Bhlhe40+/+, (2) Control mAb Bhlhe40-/-, (3) anti-PD-1 Bhlhe40+/+, (4) anti-PD-1 Bhlhe40-/-, (5) anti-CTLA-4 Bhlhe40+/+, and (6) anti-CTLA-4 Bhlhe40-/-. scRNAseq of intratumoral immune cells in BHLHE40-deficient mice revealed differential ICT-induced immune cell remodeling. These BHLHE40-dependent gene expression alterations were associated with altered metabolism, NF-kB signaling, and IFN- response in subpopulations of intratumoral CD4+ and CD8+ T cells. Intratumoral T cells from tumor-bearing Bhlhe40-/- mice also had higher transcript expression of the inhibitory receptor gene Tigit, along with altered transcript expression of chemokine/chemokine receptor granzyme family members. Bhlhe40-/- CD4+ and CD8+ T cells also had reduced ICT-driven IFN- production. Furthermore, BHLHE40 was required for ICT-induced remodeling of macrophages from a CX3CR1+ CD206+ subpopulation to an iNOS+ subpopulation. While anti-PD-1 or anti-CTLA-4 ICT in tumor-bearing Bhlhe40-/- mice led to tumor outgrowth—several BHLHE40-dependent changes were specific to the ICT treatment that was administered.

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Antitumor effects of anti-CD4-depleting antibody in lung fibrosis through CD8+ T cell activation and regulatory T cell inhibition in mice

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