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Single Cell Sequencing Analysis of Infiltrating Immune Cells in Orthotopically Implanted Liver Cancer in Mice Treated with Isotype or Anti-PD-1 Therapy

ABSTRACT: The anti-PD-1 mAb is a type of immunotherapy known to have a significant impact on tumor immune components. In this study, we utilized single-cell RNA sequencing (scRNAseq) to analyze infiltrating immune cells of liver cancer in mice treated with both anti-PD-1 and isotype control.

ORGANISM(S): Mus musculus

PROVIDER: GSE232023 | GEO | 2024/07/25

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.