The adaptive immune response to colorectal cancer (CRC) has a crucial role in prolonging host survival. Increased tumor infiltrates of CD3+ T cells can improve patient outcome, yet other T cell subsets exist that are capable of suppressing anti-tumor responses. Our lab has found that suppression of tumor-specific Th1 responses is associated with progression of CRC. Here, the phenotype and function of CD4+ T cells derived from PBMC, colon and tumor samples were analysed for suppressive markers by FACS, and anti-tumor responses by IFN-γ ELISPOT. CRC patients with more advanced tumors responded to fewer epitopes and generated a significantly weaker epitope-specific T cell response to the oncofetal antigen, 5T4 than healthy donors (p=0.0006). The mechanism of loss of T cell response is independent of HLA-DR subtype or patient age, but human depletion experiments both in vitro and in vivo indicates suppression by Foxp3+ regulatory CD4+ T cells. These cells were found in abundance amongst tumor-infiltrating lymphocytes; however, another equally prominent population of IL-10 and TGF-β-producing CD4+Foxp3- T cells were found to be >100-fold more suppressive. Thus, a major caveat to cancer immunotherapy is the suppressive tumor microenvironment, which contributes to the selective decline of measurable anti-tumor CD4+ T cell responses as tumors progress. These responses are enhanced in CRC patients by depleting regulatory T cells.
- Copyright © 2013 by The American Association of Immunologists, Inc.