IN-SITU CYTOKINE PRODUCTION BY BREAST-CANCER TUMOR-INFILTRATING LYMPHOCYTES

Background: Human breast cancers progressively grow despite the presen ce of extensive lymphocytic infiltration and specific antitumor immune recognition, thereby calling into question the competency of breast t umor-infiltrating lymphocytes (TIL). The function of breast TILs in vi vo and their possible role in the suppression of an antitumor immune r esponse are largely unknown. Methods: The cytokines produced in situ b y lymphocytes in 89 boast carcinomas and 14 benign breast lesions were assessed using immunohistochemistry. Results: The majority of tumor a nd benign breast samples contained T-cell infiltrates, which were disc losed using an anti-CD3 antibody stain. The percentage of tumor sample s in which greater than or equal to 3% of the lymphocytes were produci ng cytokines was as follows: interleukin (IL)-2 45%, IL-4 36%, tumor n ecrosis factor-alpha (TNF-alpha) 28%, transforming growth factor-beta 1 (TGF-beta(1)) 20%, IL-10 11%, interferon-gamma (IFN-gamma) 4%, and g ranulocyte-macrophage colony-stimulating factor (GM-CSF) 3%. Productio n of IL-2, IL-4, and TGF-beta(1) by TILs in breast cancers exceeded th at detected in benign breast lesions (p < 0.005). Significantly more t umor 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, I L-10, or TGF-beta(1) - were produced by lymphocytes in 44% of the spec imens, No significant associations were seen between lymphocyte produc tion of a particular cytokine and disease-free survival (median follow -up 43 months). Conclusions: Immunohistochemical techniques can be use d to detect cytokine secretion by TILs in preserved tissue. The relati ve 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 canc er is impaired.