Abstract 375: Integrin β4-targeted cancer immunotherapies

Abstract

Abstract Integrins are heterodimeric cell surface receptors that mediate interaction of cells with extracellular matrix components. Integrin β4 (ITGB4) has been reported by other investigators as a marker of cancer stem cells (CSCs). Immunological targeting of CSCs utilizing ITGB4 as a biomarker represnets a novel therapeutic opportunity to improve the efficacy of current cancer treatment. We previously reported the use of ALDH as a marker to isolate CSCs from multiple tumor types, including both human and animal tumors. In this study, we used two murine tumor models: triple-negative breast cancer (TNBC) 4T1 tumor syngeneic to Balb/c mice and SCC7 tumor which is a spontaneously arising head and neck squamous cell cancer syngeneic to C3H mice. 4T1 cells highly express ITGB4 (about 90%) in unsorted, ALDHhigh and ALDHlow cell populations. In contrast, SCC7 cells preferentially express ITGB4 on ALDHhigh CSCs because ITGB4 cell-surface abundance on ALDHhigh SCC7 cells is approximately 2-fold higher than that on ALDHlow SCC7 cells. We tested two different approaches for ITGB4-targeted immunotherapy: using ITGB4 protein as antigen to pulse dendritic cells (DC) to prepare ITGB4-DC for vaccination, or coating tumor-draining lymph node (TDLN) T cells with anti-CD3 x anti-ITGB4 bispecific antibody (ITGB4BiAb) to prepare ITGB4BiAb-T cells for adoptive transfer. We found that for the tumor which expresses ITGB4 on all the tumor cells at high level (4T1), ITGB4-targeted immunotherapies could inhibit both local tumor growth and metastasis; for the tumor which preferentially expresses ITGB4 on ALDHhigh CSCs (SCC7), ITGB4-targeted immunotherapies inhibited the tumor growth in the lung, with partial effect on local tumor. Co-current administration of anti-PD-L1 mAb significantly enhanced the therapeutic effectiveness of both approches. Our immune monitoring studies in vitro revealed that splenetic T cells harvested from mice treated with ITGB4-DC vaccine or ITGB4BiAb armed T cells mediated significant cytotoxicity against 4T1 cells and SCC7 cells, especially to ALDHhigh CSCs. In addition, ITGB4-DC vaccine or ITGB4BiAb armed T cells conferred significant host anti-ITGB4 humoral immunity as evident by produced antibodies that specifically bind and kill 4T1 cells and SCC7 cells, especially the ALDHhigh CSC population. As a result, both immunotherapeutic approaches significantly reduced the number of ALDHhigh CSCs in the residual tumor subjected to immunotherapies. In conclusion, ITGB4-targeted immunotherapies alone or combined with PD-L1 blockade demonstrated significant antitumor immunity via targeting CSCs. This may provide novel therapeutic strategies for the treatment of ITGB4-positive cancers, such as breast cancer, head and neck squamous cell carcinoma and other soilid tumors. Citation Format: Shasha Ruan, Ming Lin, Yongshun Chen, Elaine Hurt, Alfred E. Chang, Max S. Wicha, Qiao Li. Integrin β4-targeted cancer immunotherapies [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 375.