Abstract 2788: Immunological targeting of integrin β1high/β3high melanoma

Abstract

Abstract We previously reported two integrin β4 (ITGB4)-targeted immunologic strategies, e.g., ITGB4 protein-pulsed dendritic cells (ITGB4-DC) for vaccination and adoptive transfer of anti-CD3/anti-ITGB4 bispecific antibody (ITGB4 BiAb)-armed tumor draining lymph node (TDLN) T cells. Both immunotherapies significantly demonstrated efficacy in inhibiting local tumor growth and lung metastases. We found these therapeutic efficacies were closely associated with the T cell as well as humoral anti-integrin β4high cancer stem cells (CSCs) in breast (4T1) and head and neck squamous cell carcinoma (SCC7) tumor models. Recently, we further found that integrin subunits β1 (ITGB1) and β3 (ITGB3) are expressed at significantly high level in melanoma cells. In culture cell lines, integrin β1 and β3 are highly expressed on approximately 98% and 95% of the two mouse melanoma cell lines F10 and D5. We confirmed the expression of these two integrin subunits in newly harvested fresh melanoma tumors in vivo, which is very similar to the findings in cell lines. We then assessed ITGB1 and/or ITGB3-pulsed dendritic cell (DC) vaccines using F10 mouse model and demonstrated that ITGB1-DC or ITGB3-DC vaccine both exhibited significant antitumor efficacy inhibiting tumor growth, and ITGB1-DC + ITGB3-DC showed an additive/synergistic anti-tumor effect. Notably, we found that ITGB1 and ITGB3 loaded on separate DCs demonstrated more potent antitumor efficacy than loaded on the same DCs as vaccine. In addition, anti-PD-L1 significantly augmented the antitumor efficacy of ITGB1-DC/ITGB3-DC vaccine to inhibit tumor growth. Considering the crucial role of CSCs in tumor initiation, progression, metastasis, and recurrence, we further evaluated the expression of ITGB1 and ITGB3 on F10 and D5 ALDHhigh CSCs. We detected significantly higher expression of ITGB1 on ALDHhigh F10 CSCs (83.3%) and ALDHhigh D5 CSCs (87.1%) vs. ALDHlow F10 non-CSCs (0.2%) and ALDHlow D5 non-CSCs (2.0%), suggesting that ITGB1 and ITGB3-targeted vaccine-conferred anti-melanoma effects may have significantly involved targeting of ITGB1high/ITGB3high melanoma CSCs. Furthermore, recent studies suggested that bone marrow (BM)-DCs expressing dysfunctional integrin β2 (ITGB2) exhibited more potent antigen presentation function than WT BM-DCs. We found that ITGB2 highly (63.3%) expressed on the surface of BM-DC, but not on F10 or D5 tumor cells. On-going experiments include the investigation of experimental evidence to verify that ITGB1 and ITGB3-targeted vaccines have induced targeting of ITGB1high/ITGB3high melanoma CSCs; and both the cellular and humoral mechanisms underlining the anti- ITGB1high/ITGB3high melanoma CSC immunity. At the same time, generation and use of ITGB2 deficient DCs for the vaccine preparation to improve the efficacy of DC vaccine targeting integrin ITGB1high/ITGB3high melanoma and melanoma CSCs warranty further investigation. Citation Format: Feng Wang, Ying Xin, James J. Moon, Alfred E. Chang, Max Wicha, Qiao Li. Immunological targeting of integrin β1high/β3high melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2788.