Abstract PO2-25-04: Anti-TIGIT upregulate CD226 on CD8+T cell as a potential therapeutic manner in HER2 positive breast cancer
Authors: Zhang Liyi , Zhang Qi , Wang Zehao , Shao Zhibo , Xue Jingyan , Chi Yayun , Xiu Bingqiu , Wu Jiong 
Published: May 2024

Purpose: HER2 positive breast cancer subtype shows high malignancy, aggressive invasion, frequent recurrence, and low efficacy to PD-1 inhibitor though enriches in immune microenvironment. TIGIT is an immune checkpoint which expresses on T/NK cells and participates in immune evasion of cancer cells. Here, we investigated the effect of anti-HER2 and anti-TIGIT combination regarding to HER2 breast cancer treatment and tumor microenvironment, further exploring mechanisms behind the combination utilization.

Methods: We re-analyzed the untreated human and mouse HER2 breast cancer scRNA-seq dataset to explore proportions of unique cell clusters in tumor immune microenvironment and communicated signals between immune cells and tumor cells. Mouse HER2 non-sensitive model and 27 non-pCR patients were utilized to investigate the variation of TIGIT and its ligand CD112/CD155 in HER2 non-sensitive population. Relevance between CD112/CD155 and prognosis was verified by 200 patients tissue microarray IHC. We validated the efficacy of combination of anti-TIGIT and anti-Neu and delineated scRNA-seq landscape via mouse model. Multilayer analysis including CellChat and AuCell were used to investigate difference of immune network between ctrl group, monotherapy and combination. In vitro and in vivo studies were used to verify the efficacy of anti-TIGIT and pivotal clusters.

Results: We found that CD8+T cells occupied major proportion in TILs in both human and mouse HER2 breast cancer tumor immune microenvironment. CD8+T cells showed TIGIT signal to malignant epithelial cells instead of PD-1 signal. Increased CD8+TIGIT+T cells were related to poor prognosis in 200-patients cohort. In HER2 non-sensitive mouse model, significantly increased CD8+TIGIT+T cells were found in HER2 non-sensitive group. Multiplex IHF of 27 non-pCR patients also confirmed that CD8+TIGIT+T cells increased after treatment. CD112, ligand of TIGIT on malignant cells, demonstrated higher expression after anti-HER2 treatment in HER2 non-sensitive population and negatively correlated with prognosis. In scRNA-seq about control group, monotherapy and combination group, we defined malignant cells as sensitive subclone, Neu resistant subclone and others according to cell ratio variation in ctrl, monotherapy and combination group. CD112 upregulated in all subclones in monotherapy group. GSVA analysis indicated Neu resistant subclone had highest IFN-γ response among subclones. In Neu resistant subclone, combination group showed highest expression of MHC-I genes and upregulated IFN-γresponse, suggested the restored antigen presenting ability of Neu resistant subclone. Higher CD226, MHC-I and IFN-γ signals between malignant epithelial cells and CD8+T cells was found in combination group via CellChat. AuCell manifested upregulated T cell activation and IFN-γ production pathways in combination group. Public dataset showed favorable results. Increased CD226 expression and promoted cytotoxicity on CD8+T cells can only be induced by anti-TIGIT therapy in vitro and in vivo. 200-patients cohort indicated the predictive values of CD8+CD226+T cells in HER2 breast cancer.

Conclusion: In conclusion, engaged immune checkpoint TIGIT shades malignant cells from CD8+T mediated immune surveillance in HER2 breast cancer. Disruption of TIGIT inhibit tumor growth in vivo by immune elimination of malignant cells. Besides, CD8+CD226+T cells induced by combined therapy can predict patient prognosis.

Citation Format: Liyi Zhang, Qi Zhang, Zehao Wang, Zhibo Shao, Jingyan Xue, Yayun Chi, Bingqiu Xiu, Jiong Wu. Anti-TIGIT upregulate CD226 on CD8+T cell as a potential therapeutic manner in HER2 positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-25-04.