Kim, Betty Y.

Abstract The discovery of immune checkpoint blockades have resulted in significant clinical benefits for patients with metastatic cancers including non-small cell lung cancer (NSCLC). Nevertheless, a large proportion of patients do not respond to such therapy. Strategies to enhance the therapeutic efficacy of cancer immunotherapy among a larger group of patients are urgently needed. Increasing the recognition of cancer cells by immune system may enhance response to immunotherapies. Tumor-associated macrophage (TAM) is the most abundant immune cell in most solid tumors, and is critical in bridging innate and adaptive immune system functions. Cancer cells overexpress multiple immune suppressive molecules including phosphatidylserine (PS) to inhibit immunological functions of TAMs. PS expression can be enhanced by cancer therapeutics such as radiation to induce immune suppression. Our results show that radiation increased expression of PS on lung cancer cells. The combination of PS blocking antibody with radiation decreased immune-suppressive phagocytosis and enhanced antigen presentation of macrophages. In murine lung cancer models, combination treatment of PS blockade and chemoradiation more effectively controlled tumor growth and prolonged survival than each treatment used alone. In a bilateral lung cancer tumor model, addition of PS blockade to chemoradiation promoted cytotoxic T cell infiltration and induced tumor growth inhibition of the non-irradiated tumors. Together, our results demonstrate that PS-targeting antibodies may be combined with chemoradiation to enhance intrinsic tumor immunogenicity and activate systemic anti-tumor immune responses. This approach may provide new routes for improving the efficacy of modern immunotherapeutics. Citation Format: Yifan Wang, Zhigang Liu, Weiye Deng, Betty Y. Kim, Steven H. Lin, Wen Jiang. Phosphatidylserine-targeting antibody combined with chemoradiation enhances systemtic anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 530.

Abstract While growing evidence suggests that tumor microenvironment can modulate stemness and the mesenchymal phenotype, little is known about how these cell states are coordinately regulated. We report that S100A4 controls both stemness and mesenchymal transition in GBM cells. In a spontaneous mouse glioma model and in primary human GBM tumorspheres, S100A4 expression is enriched in tumor-initiating cells and is required for self-renewal and tumor growth in vivo. In addition, greater than 80 percent of S100A4+ cells are associated with the tumor vasculature, a known niche for glioma stem cells, and S100A4 promotes pro-angiogenic factor expression. Interestingly, acidosis induces expression of S100A4 and the EMT regulators SNAIL1/2 and acidosis-induced EMT regulator expression requires S100A4 function. Importantly, S100A4 functions as a molecular switch between the proneural and mesenchymal states in GBM as S100A4 knockdown results in down-regulation of the mesenchymal signature genes, including the “master transcriptional regulators of mesenchymal transition”, and concurrent up-regulation of proneural signature genes. Together, these results indicate that S100A4 sits in a critical node in the molecular network that controls both glioma stem cells and the mesenchymal phenotype. Citation Format: Kin-Hoe Chow, Hee Jung Park, Joshy George, Yuanxin Chen, Andrew Gallup, Wen Jiang, Betty Y. Kim, Kyuson Yun. Regulation of GBM stemness and mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4783. doi:10.1158/1538-7445.AM2017-4783