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

<p>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.</p><p>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.</p><p>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.</p><p>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.</p><p>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 down- regulated 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.</p><p>The findings presented here show that various mechanisms of tumor- mediated 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.</p><h3>List of scientific papers</h3><p>I. Poschke I, Mougiakakos D, Hansson J, Masucci GV, Kiessling R. Immature immuno-suppressive CD14+ HLA-DR-/low cells in melanoma patients are Stat3 hi and overexpress CD80, CD83 and DC-Sign. Cancer Research. 2010; 70(11):4335-4345. <br><a href="https://doi.org/10.1158/0008-5472.CAN-09-3767">https://doi.org/10.1158/0008-5472.CAN-09-3767</a><br><br> </p><p>II. Poschke I, Mao Y, Adamson L, Salazar-Onfray F, Masucci GV, Kiessling R. Myeloid-derived suppressor cells impair the quality of dendritic cell vaccines. Cancer Immunology, Immunotherapy. 2011. [Accepted] <br><a href="https://pubmed.ncbi.nlm.nih.gov/22080405">https://pubmed.ncbi.nlm.nih.gov/22080405</a><br><br> </p><p>III. Poschke I, De Boniface J, Mao Y, Kiessling R. Tumor-dependent down-regulation of the ζ-chain in T cells is detectable in early-stage breast cancer patients and correlates with immune cell function. International Journal of Cancer. 2011. [Accepted] <br><a href="https://pubmed.ncbi.nlm.nih.gov/21823123">https://pubmed.ncbi.nlm.nih.gov/21823123</a><br><br> </p><p>IV. Poschke I, De Boniface J, Mao Y, Kiessling R. Tumor-induced changes in the phenotype of blood-derived and tumor-associated T cells of earlystage breast cancer patients. [Manuscript]</p>