Abstract 5368: Targeting tumor-intrinsic S100A1 augments antitumour immunity and potentiates anti-PD-1 efficacy
Authors: Guo Yufeng , Bai Hua , Wang Jie 
Published: March 2024

Abstract
Immune-checkpoint blockade (ICB) has revolutionized cancer treatment. However, only a minority of patients achieve the long-term, durable response to ICB, and the response rates in most advanced tumors is limited to 10%-25%. The unsatisfactory overall response to ICB and the great variation in response among individuals highlight the necessity for developing predictive biomarkers and overcoming ICB resistance. A potential mode of resistance is tumor-mediated immunosuppression leading to inhibition of T cell-mediated infiltration and immunity. Here, combining single-cell and bulk transcriptomic analysis with liquid biopsy of tumor patients, we showed that S100 calcium binding protein A1 (S100A1) was closely related to ICB response, and that detecting plasma S100A1 level could help predicting the response to ICB, implying that tumor-intrinsic S100A1 may contribute to immunosuppressive tumor microenvironment (TME) and resistance to ICB. Importantly, endogenous S100a1 knockdown (S100a1KD) promoted anti-tumor immunity, conferred tumor regression, and sensitized tumors to anti-PD-1 immunotherapy in multiple syngeneic murine models. By characterizing the immune landscape of S100a1KD syngeneic murine tumor models and non-small cell lung cancer (NSCLC) clinical samples, we demonstrated a negative relationship between tumor-intrinsic S100A1 expression and infiltration of M1-like macrophage and CD8+ T cells. Single cell and spatial transcriptomic analyses, together with functional studies, have revealed that ablation of tumor-intrinsic S100A1 exerts profound impacts on the M1-like polarization of macrophages and cytotoxicity of CD8+ T cells. Moreover, the conditioned medium from S100a1KD tumor cells promoted M1 polarization of both bone marrow-derived macrophages (BMDMs) and Raw264.7 cells, which in turn reinvigorated tumor-specific T cell immunity both in vitro and in vivo. Of note, as a secreted protein, introducing recombinant S100A1 into the medium from S100a1KD tumor cells could not reverse the effects on T cells and macrophages, suggesting that these effects were independent of extracelluar S100A1 secretion and that S100A1 may act as an intracellular signaling molecule. Mechanistically, S100A1 affects deubiquitination of NF-κB through interacting with the ubiquitin-like (Ubl) domains of ubiquitin specific protease 7 (USP7), leading to upregulated granulocyte-macrophage colony-stimulating factor (GM-CSF) expression. Collectively, these data identified the S100A1/USP7/p65/GM-CSF inhibitory axis as a critical immune suppressor on M1-like macrophage polarization and T cell immunity for the promotion of tumor progression and resistance to ICB. Our findings demonstrated the potential of plasma S100A1 expression in predicting the response to ICB, and provide a rationale for combining GM-CSF and anti-PD-1 immunotherapy in tumors with high S100A1 expression.
Citation Format: Yufeng Guo, Hua Bai, Jie Wang. Targeting tumor-intrinsic S100A1 augments antitumour immunity and potentiates anti-PD-1 efficacy [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 5368.