Abstract B063: Targeting the pathogenic mesenchymal stem cells as a new strategy for preventing immune dysfunction in cancer therapy

The immune system is exhausted by persistent and chronic inflammation due to internal and external stimuli, and ultimately loses the functions contributing to the pathogenesis of cancer. T-cell dysfunction is fatal to immunotherapy designed to elicit and intensify immune responses against cancer, and it is a crucial issue beyond immunosuppression that is recoverable by breaking immune checkpoint pathways. Although increase of exhausted T cells has been demonstrated in inflammatory cancer and aging, the reasons for the immune dysfunction and the methods for overcoming it remain undefined. In this study, we attempted to elucidate the underlying mechanisms involved in the immune exhaustion. We compared cell population and immune responses of spleen cells and bone marrow cells between young (1- to 4-month-old) and aged (18- to 24-month-old) C57BL/6 mice implanted with/without murine tumor cells such as melanoma B16-F10 and lung cancer 3LL. We found that CD45-CD166+ activated mesenchymal stromal/stem cells (MSCs) increased in the spleen and bone marrow of mice with age, correlatively with increase of CD3+PD1+Tim3+ exhausted T cells having no cytotoxic activities, and were further expanded by implantation with tumor cells. The MSCs sorted from aged mice generated the CD3+PD1+Tim3+ exhausted T cells as well as immunosuppressive Tregs and MDSCs when cocultured in vitro, and transfer with these MSCs promoted in vivo tumor growth via systemic expansion of exhausted T cells in young mice, although none or less of such properties were seen using the young MSCs. Interestingly, the aged MSCs frequently differentiated into hypertrophic adipocytes with a large lipid droplet containing a huge amount of inflammatory cytokines, implying acceleration of the immune exhaustion after adipogenic differentiation in aged mice. These suggest the key role of the increasing MSCs in deterioration of T-cell responses with age. We identified the specific molecules significantly upregulated in the aged MSCs by utilizing cDNA microarray analysis. Blocking the gene expressions using the specific siRNAs corrected unbalanced immunity through decline of immune suppression and exhaustion in the aged mice, and generated potent tumor-specific CTLs resulting in tumor regression, although immune checkpoint inhibitors are ineffective in the same settings. These results suggest that increase of the pathogenic MSCs might be a risk factor of resistance to immune checkpoint inhibitors, and targeting these MSCs may be a promising strategy for creating a suitable immune status for eliminating cancer. Citation Format: Chie Kudo-Saito, Yamato Ogiwara, Kazunori Aoki. Targeting the pathogenic mesenchymal stem cells as a new strategy for preventing immune dysfunction in cancer therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B063.