Escalating Regulation Of 5t4-Specific Ifn-Gamma(+) Cd4(+) T Cells Distinguishes Colorectal Cancer Patients From Healthy Controls And Provides A Target For In Vivo Therapy

The relationship between the adaptive CD4(+) T-cell response and human cancer is unclear. The oncofetal antigen 5T4 is expressed in many human carcinomas, including colorectal cancer cells, but has limited expression on normal tissues. We previously identified anti-5T4 CD4(+) T cells in a proportion of patients with colorectal cancer, and we extended this study to examine whether the quality or quantity of the T-cell response reflects tumor stage. An overlapping peptide library spanning 5T4 was used as a target to enumerate cognate IFN-gamma(+) CD4(+) T cells [measured as spot-forming cells (SFC)/10(5) cultured T cells] in peripheral blood-derived lymphocytes following a 14-day in vitro culture period comparing patients preoperatively (n = 27) to healthy controls (n = 17). Robust 5T4-specific T-cell responses were present in 100% of healthy donors. There was a steady loss of T-cell responses with advancing tumors with a significant negative correlation from stage I to III (P = 0.008). The predictability of the decline meant <200 SFC/10(5) were only found in subjects with stage III colorectal cancer. The mechanism of loss of T-cell response is independent of HLA-DR type or patient age but does correspond to increases in Foxp3(+) regulatory T cells (Treg). Using low-dose cyclophosphamide to reduce the proportion of Tregs in vivo resulted in increased anti-5T4 T-cell responses in patients with colorectal cancer. The selective loss of 5T4-specific IFN-gamma(+) CD4(+) T-cell responses implies a link between tumor stage and antitumor Th1 effector function; depleting Tregs can enhance such responses. (C) 2013 AACR.