Tumor-mediated changes in the immune system of cancer patients - a balancing act between suppressors and effectors

Abstract: Tumors and immune cells interact in many ways: immune cells can recognize and even kill tumor cells, while the tumor on the other hand can induce cells of the immune system to participate in tumor-mediated immune subversion. We studied immunosuppressive effects that human tumors exert on immune effector cells, particularly T cells, by inducing suppressive myeloid cells and decreasing T cell functional capacity. Increased numbers of myeloid-derived suppressor cells (MDSC) have been found in tumor-bearing individuals in response to cancer-derived factors. We characterized a CD14 + HLA-DR -/low MDSC population in patients with melanoma that could strongly suppress T cell function. Suppressive activity was dependent on cell-cell contact, arginase-1 expression, oxidative stress, and STAT3 signaling. Melanoma MDSC exhibited a mixed phenotype including markers of both mature and immature cells. Due to their monocyte-like characteristics, we wondered whether the presence of MDSC could interfere with the generation of monocyte-derived dendritic cells (DC) for vaccine use. We found that melanoma MDSC exerted a dose-dependent negative effect on DC quality. The removal of MDSC from monocytes prior to DC generation could therefore be advisable in order to improve vaccine efficacy in diseases where CD14 + HLA-DR -/low cells have been observed. Tumor-mediated immunosuppression has mostly been studied in patients with advanced cancer, thereby under-representing the group of early-stage cancer patients that should have a better chance to mount anti-tumor immunity and benefit from tumor immunotherapy. We found that even patients with early-stage breast cancer exhibit signs of tumor-induced immune modulation. Expression of the ζ-chain, an important transducer of activating signals in T and NK cells, was downregulated in patients compared with controls, but normalized after surgical tumor removal. Loss of ζ-chain expression was detectable in the blood, but strongest in the tumor, suggesting it to be mediated by tumor-derived factors. Further, circulating T cells of breast cancer patients were more differentiated than those of controls and exhibited signs of altered homing capacity. Tumor-associated T cells were dominated by effector memory cells that showed signs of activation, but were accompanied by indicators of immunosuppression. The findings presented here show that various mechanisms of tumormediated immunosuppression are active in patients with early- as well as late-stage cancers. Understanding such tumor-immune interactions is the first step towards the design and optimization of immunotherapeutic strategies for the treatment of cancer.

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