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Abstract Immune checkpoint inhibitors (ICIs) targeting immune modulatory molecules have been widely used and have shown therapeutic efficacy in treating multiple malignancies in the last decade. However, in triple-negative breast cancer (TNBC), only around 5 % of patients showed a durable response to ICIs. While the response rates were increased up to 10% by combining ICIs with conventional chemotherapy, the majority of the patients did not respond to the treatment. Thus, there is a need to improve our understanding of the mechanism underlying unequal response to ICIs in TNBC and develop/discover new treatments to improve patient outcomes. The lack of response to ICIs has been attributed to the increased infiltration of immunosuppressive cells (including MDSCs, neutrophils and TAMs), as well as the presence of additional immune checkpoint receptors/ligands that may further suppress cytotoxic T cells (CD8+ T cells) in the tumor microenvironment (TME). V-domain Ig suppressor of T-cell activation (VISTA) is one of the immune checkpoint molecules attracting increasing attention in the context of anti-tumor immunity due to its broad expression across various cancer types and increased expression upon development of immune checkpoint resistance. However, the role of VISTA in the anti-tumor immune response and its therapeutic potential in TNBC remains unclear. In our study, we observed that VISTA is expressed in TNBC patients, with higher expression in neutrophils and macrophages. In the Py230 murine breast cancer model, VISTA expression increased upon paclitaxel (PTX), anti-PD-L1 and paclitaxel combined with anti-PD-L1 treatment compared to the control group, suggesting its potential role as a resistance mechanism in further inhibiting T cells. In the Py230 model, VISTA blockade increased the infiltration and activation of CD8+ T cells, as evidenced by the higher number of CD8+ T cells, increased CD69+CD8+ T cells, and Granzyme B production, indicating that VISTA blockade improved CD8+ T cells mediated anti-tumor immunity. To functionally test the role of VISTA, we stimulated CD8+ T cells and co-cultured them with naïve macrophages or tumor educated macrophages in the presence or absence of VISTA blocking antibody. Tumor-educated macrophages showed increased immunosuppressive activity which is abrogated with VISTA blockade. Moreover, we found that the immunosuppressive effect of macrophages on T cell activation needs direct cell interaction between VISTA on macrophages and T cells. In conclusion, this study shows the mechanism of action of VISTA in the regulation of T cells mediated anti-tumor immune response, and provides the rationale for blocking VISTA in TNBC. Citation Format: Maidinaimu Abudula, Yuliana Astuti, Meirion Raymant, Teifion Luckett, Patrick Freeman, Michael Schmid, Ainhoa Mielgo Iza. Understanding the role of VISTA in regulating T cells function and the therapeutic potential of blocking VISTA in triple negative breast cancer 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 (6Suppl): Abstract nr 1518.
Abudula et al. (Fri,) studied this question.