Transcriptomic profiling of PBMCs from mammary tumor dogs reveals two distinct immune states.

This study analyzed cancer-specific systemic immune responses in peripheral blood mononuclear cells (PBMCs) from dogs with benign tumors, malignant tumors, and normal conditions. By examining gene expression patterns - particularly immune checkpoint and TNFRSF genes - the study aimed to assess the immune state of cancer PBMCs. Surprisingly, half of the tumor PBMCs exhibited downregulation of both immunosuppressive genes (Pdcd1, Ctla4, Tigit) and immune activation molecules (CD27, CD357), suggesting immune inactivity rather than suppression. Additionally, cytokine expression varied significantly, with upregulation of IL-18 and IL-7, despite their controversial roles in tumor progression. Analysis of T-cell exhaustion markers did not reflect established exhaustion signatures, implying a naive-like immune state. Instead, a distinct immune signature emerged, characterized by the broad downregulation of TNFRSF genes (TNFRSF18, TNFRSF14, TNFRSF6, and CD27). We designated this group as PI (PBMC-impaired). Deconvolution of bulk RNA-seq data further revealed a significant reduction in CD4+ T cells and a lower CD4+/CD8+ ratio in the PI group. Gene Ontology (GO) and pathway analyses linked CD4+ cell differentially expressed genes (DEGs) to regulatory T-cell differentiation, inflammatory responses, and key immune pathways (IL-2/STAT5, NF-kappa B). Notably, CD7, CXCL6, FASN, FLT3LG, LTB, and TNFRSF18 were significantly downregulated, marking a potential transcriptomic signature of systemic immune impairment. These findings suggest that immune dysfunction in the PI group is not solely attributable to conventional immune suppression but rather to a diminished immune activation state driven by reduced TNFRSF gene expression.