In situ cytokine production by breast cancer tumor-infiltrating lymphocytes.

Abstract

Human breast cancers progressively grow despite the presence of extensive lymphocytic infiltration and specific antitumor immune recognition, thereby calling into question the competency of breast tumor-infiltrating lymphocytes (TIL). The function of breast TILs in vivo and their possible role in the suppression of an antitumor immune response are largely unknown. The cytokines produced in situ by lymphocytes in 89 breast carcinomas and 14 benign breast lesions were assessed using immunohistochemistry. The majority of tumor and benign breast samples contained T-cell infiltrates, which were disclosed using an anti-CD3 antibody stain. The percentage of tumor samples in which > or =3% of the lymphocytes were producing cytokines was as follows: interleukin (IL)-2 45%, IL-4 36%, tumor necrosis factor-alpha (TNF-alpha) 28%, transforming growth factor-beta 1 (TGF-beta 1) 20%, IL-10 11%, interferon-gamma (IFN-gamma) 4%, and granulocyte-macrophage colony-stimulating factor (GM-CSF) 3%. Production of IL-2, IL-4, and TGF-beta 1 by TILs in breast cancers exceeded that detected in benign breast lesions (p < 0.005). Significantly more tumor samples contained lymphocytes producing IL-2, IL-4, TGF-beta 1, and TNF-alpha than IFN-gamma and GM-CSF (p < 0.002 for each comparison). One or more of the potentially immunoinhibitory cytokines-IL-4, IL-10, or TGF-beta 1-were produced by lymphocytes in 44% of the specimens. No significant associations were seen between lymphocyte production of a particular cytokine and disease-free survival (median follow-up 43 months). Immunohistochemical techniques can be used to detect cytokine secretion by TILs in preserved tissue. The relative lack of secretion of IFN-gamma and GM-CSF, rather than a deficiency of IL-2, may explain why the antitumor immune response to breast cancer is impaired.