Expansion of CD3+CD56+ lymphocytes correlates with induction of cytotoxicity by interleukin-2 gene transfer in human breast tumor cultures.

BACKGROUND

Mice immunized with murine mammary carcinoma cells genetically engineered to secrete interleukin-2 (IL-2) are rendered resistant to subsequent challenge with unmodified tumor cells, and in the case of mice bearing established tumors, the rate of development of pulmonary metastases is reduced. Despite these encouraging animal results, little is known about the induction of antitumor immunity by IL-2 gene transfer in human breast cancer.

METHODS

Adenovirally mediated IL-2 gene transfer was performed in 12 tumor fragment cultures established from seven primary breast cancers. Autologous tumor infiltrating lymphocytes (TILs) or peripheral blood mononuclear cells (PBMCs) were cocultured with transduced tumor fragments, and changes in phenotype and cytotoxicity were measured.

RESULTS

IL-2 was never detectable in the untransduced cultures, but it peaked at 5.0-1,324.8 ng/ml in the transduced cultures. Lymphocyte counts declined in all untransduced cultures, but they increased two- to sevenfold in four transduced cultures. CD4:CD8 ratios decreased from a mean of 2.11 at baseline to 1.27 after stimulation in coculture (p = 0.03). Expansion of lymphocytes expressing the natural killer cell phenotype (CD3-CD56+) occurred in only one culture, but the CD3+CD56+ population increased in four of six cultures. Lymphocytes from four of 10 cocultures generated significant cytotoxicity against allogeneic breast cancer cells. Induction of cytotoxicity correlated with expansion of the CD3+CD56+ phenotype (R2 = 0.805, p = 0.02).

CONCLUSIONS

IL-2 gene expression by human breast cancer causes expansion of CD3+CD56+ cytotoxic-lymphocytes. This phenotype is consistent with that of a non-major histocompatibility complex (MHC)-restricted cytokine induced killer cell population previously described.