Innate Immune Correlates of Sickness-Like Depressive Symptoms in Breast Cancer Survivors

Abstract

Background: Research supports immune pathways of depression characterized by sickness-like symptoms (e.g., appetite changes, low energy, sleep disturbance, difficulty initiating activity, concentration difficulties), with limited evidence for negative affect symptoms (e.g., depressed mood, feeling of failure). However, most findings come from otherwise healthy individuals, limiting generalizability to medical populations. This study leveraged breast cancer as a disease context, given the lasting cancer- and treatment-related effects on immune function, to examine the hypothesis that proinflammatory gene expression relates more strongly to sickness-like than negative affect symptoms. Methods: Data were drawn from 175 women with Stage 0-III breast cancer (Mage=55.3 years) assessed at five time points from diagnosis through 18 months post-treatment. Depressive symptom dimensions were assessed using the Center for Epidemiologic Studies Depression Scale. Peripheral blood mononuclear cell gene expression was assessed using RNA sequencing-based transcriptional profiling. Primary analyses focused on proinflammatory gene expression. Exploratory analyses examined Type-I interferon gene expression and transcript-derived cell-type composition (myeloid-to-lymphoid and classical-to-non-classical monocyte ratios). Results: Longitudinal mixed-effects models across repeated assessment revealed that greater sickness-like symptom severity was associated with elevated proinflammatory gene expression (p<.001), Type-I Interferon antiviral gene expression (p<.001), myeloid cell abundance (p<.001), and particularly non-classical monocytes (p=.002). By contrast, negative affect symptoms showed weaker, null, or opposite associations. Conclusions: Sickness-like and negative affect symptoms show divergent associations with innate immune system activation and myeloid lineage bias. Results may inform more targeted interventions for both physical/energetic and psychological symptoms in breast cancer survivors, and may be relevant to other depression and medical contexts.