Systemic Immune Remodeling in Breast Cancer: Selective Enrichment of TNFR2⁺ Circulating Lymphocytes in Breast Cancer

Tumor necrosis factor-alpha (TNF-α) exerts both tumor-promoting and tumor-suppressive effects in breast cancer through its two molecular forms, transmembrane (tmTNF-α) and soluble (sTNF-α), which signal via distinct receptors, TNFR1 and TNFR2. While TNFR1 is minimally expressed on lymphocytes within tumor-draining lymph nodes, TNFR2 predominates on B and T cells, highlighting its key role in immune regulation. Considering that cancer affects systemic immunity, this study assessed TNFR2 expression on circulating lymphocytes in breast cancer patients to elucidate immune alterations across disease stages.

Peripheral blood was collected from 50 women with histologically confirmed breast cancer and 24 age-matched healthy volunteers. Lymphocytes were isolated using density gradient centrifugation, and TNFR2 expression on B and T cell subsets was evaluated by flow cytometry with specific monoclonal antibodies.

Patients exhibited marked lymphopenia, with significantly reduced frequencies of CD19⁺ B cells, CD3⁺ T cells, and CD4⁺ T cells (all p < 0.001), a pattern present even in patients without lymph node involvement. In contrast, CD3^-CD8⁺ cells were increased, consistent with expansion of innate lymphocytes. Despite overall lymphocyte decline, the proportion of TNFR2⁺ cells was elevated in patients, including CD19⁺TNFR2⁺ B cells (p = 0.036) and CD3⁺TNFR2⁺ T cells (p = 0.009), with a borderline rise in CD4⁺TNFR2⁺ T cells (p = 0.061). These immune alterations were observed across multiple clinical subgroups, though with distinct patterns, such as enrichment of TNFR2⁺ T cells in LN⁺ patients and higher TNFR2⁺ B-cell frequencies in LN- patients.

Elevated TNFR2 expression on peripheral lymphocytes, despite overall lymphocyte depletion, underscores its potential as a biomarker and immunomodulatory target in breast cancer progression.