Atrophied thymus negatively affects cancer chemo-immunotherapy
Olga Sizova, Jiyoung Oh, Denis Kuriatnikov and Dong-Ming Su*
Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, 76107 USA
Tumor metastatic relapse is responsible for main cancer-associated mortality and potentially due to undetectable minimal numbers of tumor cells, which are able to resist adjuvant radio-chemotherapy at a dormant status hiding in certain organs (termed: cancer reservoirs). A central T cell immune organ, the thymus, has been suggested as a kind of pre-metastatic cancer reservoir for B-lymphoma cells, which are a risk for eventual recurrence. In addition, chemotherapy-resulted thymic atrophy could relatively enhance tumor-associated antigen (TAA)-specific thymic regulatory T cell (tTreg) generation, thereby potentially increasing suppression of antitumor immunity and hampering thorough eradication of hidden minimal tumor cells. We determined that circulating melanoma (solid tumor) cells were also able to be retained in the thymus, in addition to lymphoma. The retention proportion was increased in the atrophied thymus. Chemotherapy (doxorubicin)-altered thymic microenvironment exhibited increased pro-inflammatory factors: IL6, IL1β and TNFα, which establish conditions to induce tumor cell chemo-resistant dormancy. We found that the increased pro-inflammatory factors were due to DNA-damage response-triggered p53 activation in non-malignant thymic cells, which induced thymocyte death and thymic epithelial cell senescence, resulting in activation of SASP (senescence-associated secretory phenotype). Furthermore, chemotherapy modifies thymic microenvironment to decline autoimmune regulator Aire gene expression, thereby relatively enhancing TAA-tTreg generation due to a reduced TCR signaling strength for thymcoyte negative selection and an increased intermediate TCR signaling. This resulted in an increased infiltration of TAA-specific Treg cells in tumor mass. The outcome should be difficult to eradicate undetectable minimal numbers of tumor cells in their reservoirs. Our finding demonstrated that the atrophied thymus, which elicits events to negatively affect cancer chemo-immunotherapy, should be a novel target in antitumor therapy and preventing from tumor metastatic relapse.