Regression of a Mammary Adenocarcinoma in STAT6−/− Mice Is Dependent on the Presence of STAT6-Reactive T Cells

Abstract

Polarization of the immune response toward a type 1 cytokine profile has been posited to be associated with a therapeutic antitumor immune response. STAT6−/− mice are unable to generate a type 2 immune response, and instead mount an enhanced type 1 response. STAT6−/− mice are significantly more resistant to 4T1, a mammary adenocarinoma cell line, resisting a 10-fold higher tumor dose compared with wild-type (wt) BALB/c mice. An analysis of the T cells from tumor-bearing STAT6−/− mice revealed that they contained a population primed by a peptide (STAT6531–539) of the STAT6 protein expressed in 4T1. The adoptive transfer of T cells from STAT6531–539-vaccinated STAT6−/− mice significantly reduced the number of 4T1 pulmonary metastases in recipient mice. Additionally, the role of these STAT6531–539-reactive T cells against s.c. 4T1 tumor challenge was determined by tumor-challenging wt BALB/c mice reconstituted with STAT6−/− bone marrow, thereby assessing whether a polarized type 1 immune response in the absence of STAT6-reactive T cells was sufficient to reject a 4T1 tumor challenge. T cells from the STAT6−/− bone marrow chimeras failed to recognize the STAT6531–539, and these mice proved to be as susceptible as wt BALB/c mice to 4T1 challenge. This demonstrated that the absence of STAT6531–539-reactive T cells correlated with the inability to reject 4T1 challenge. Additionally, these data emphasize that the enhanced ability to mount a type 1-polarized immune response is inconsequential if a sufficient antitumor immune response is not primed by the tumor.