Abstract 708: Increase of senescent mesenchymal stromal/stem cells is predictive of unresponsiveness to the treatment with immune checkpoint inhibitors
Authors: Kudo-Saito Chie , Miyamoto Takahiro , Kawamura Mami , Ogiwara Yamato , Aoki Kazunori 
Published: August 2018

Purposes: The therapeutic efficacy induced by immune inhibitory checkpoint inhibitors is still limited to a part pf the treated patients, and the methods effective in overcoming the treatment failures have not been established yet. A main issue under discussion is immune exhaustion as well as immune senescence with age, which is caused by persistent and chronic inflammation due to both internal and external stimuli ultimately leading to immune dysfunction in cancer patients. In literature, aging has been reported as a strong risk factor not only for causing cancers, but also for inducing hyper progression after treatment with immune checkpoint inhibitors in clinical settings. This suggests that a distinct strategy from releasing the brake on immune suppression might be needed for properly organizing anti-tumor immunity in aged hosts. In this study, we attempted to elucidate the molecular mechanisms underlying the immune exhaustion with age.

Results: We used young (1 to 4-month-old) and aged (18 to 24-month-old) C57BL/6 mice, and comprehensively analyzed cell population and immune responses of spleen cells and bone marrow cells obtained from the mice. With age, CD45-CD166+ mesenchymal stromal/stem cells (MSCs) increased correlatively with increase of immunosuppressive CD4+CTLA4+Foxp3+ Tregs and CD11b+Gr1+ MDSCs, and dysfunctional CD3+PD1+Tim3+ T cells in mice. These cells were further expanded by implanting with tumor cells such as melanoma B16-F10 and lung cancer 3LL, and immune checkpoint inhibitors were ineffective in suppressing tumor progression in aged mice. As compared to the young MSCs, the aged MSCs generated much more dysfunctional T cells in vitro and in vivo, and differentiated into hypertrophic adipocytes with a large lipid droplet containing a huge amount of inflammatory adipokines. These suggest that the increasing MSCs play a key role in disturbing anti-tumor immunity both before and after differentiation in aged hosts. Utilizing cDNA microarray analysis, we identified the specific molecules those are significantly upregulated in the aged MSCs, but not young MSCs. Knockdown of the gene expressions in the aged MSCs using the specific siRNAs deprived of the morbid properties, and generated potent tumor-specific CTLs through balancing immunity in the aged mice.

Conclusions: These results demonstrate that increase of the senescent and inflammatory MSCs are, at least in part, responsible for the unresponsiveness to the treatment with immune checkpoint inhibitors. Elimination of these MSCs may be a promising strategy for successfully controlling immunity against cancer.

Citation Format: Chie Kudo-Saito, Takahiro Miyamoto, Mami Kawamura, Yamato Ogiwara, Kazunori Aoki. Increase of senescent mesenchymal stromal/stem cells is predictive of unresponsiveness to the treatment with immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 708.