Abstract Introduction: Acute myeloid leukemia (AML) has largely evaded clinical benefit from immunotherapeutic approaches, with current CAR-T therapies targeting CD123 and CD33 showing limited activity and significant cytopenia due to shared antigen expression with normal hematopoietic stem cells. While the standard 7+3 chemotherapy regimen has remained unchanged for over four decades, its immunomodulatory effects remain poorly understood. Here, we demonstrate that chemotherapy induces expression of CD70, a TNF family ligand with low expression in normal hematopoietic stem and progenitor cells (5%) compared to AML cells, making it an attractive immunotherapeutic target. Methods: Using genome-wide CRISPR knockout screening, we identified p53 as the master regulator of CD70 expression in AML cells. Chemical activation of p53 with Nutlin-3 or chemotherapy agents significantly increased CD70 surface expression in p53 wild-type but not p53-inactivated AML cell lines. In syngeneic mouse models, p53-knockout MLL-AF9 AML cells overexpressing mouse CD70 failed to engraft in immunocompetent C57BL/6 mice while expanding normally in immunodeficient NSG mice, demonstrating CD70's immune-activating role. NK cell depletion with anti-Asialo-GM1 antibodies restored engraftment, confirming that CD70 triggers NK cell-mediated immune responses. In vitro studies using human MV4-11 cells revealed that CD70 knockout significantly impaired T cell-mediated cytotoxicity and reduced T cell activation. Results: To translate these findings, we generated CD70-directed CAR-T cells and demonstrated that p53-activating agents enhance their anti-leukemic efficacy. Analysis of primary AML patient samples (n=47) revealed significantly higher CD70 expression in TP53 wild-type compared to TP53-mutant samples following chemotherapy, with CD70 levels correlating with time from chemotherapy administration. Retrospective analysis of AML patients showed significantly better outcomes in those with wild-type TP53 and high CD70 expression post-chemotherapy. Conclusion: Together, our findings reveal a novel mechanism by which TP53 mutations drive immune evasion in AML and supports combining CD70-targeted immunotherapy with chemotherapy or p53-activating agents to overcome current limitations in AML treatment. Citation Format: Chuqi Wang, Jordan Yong Ming Tan, Previtha Dawn Sakthi Vale, Nishtha Chitkara, Fang Qi Lim, Yuhan Wang, Xiao Xian Lin, Karanpreet Singh Bhatia, Yash Manish Agrawal, Wen Kang Soh, Gloryn Chia, Nicholas R. J. Gascoigne, Shruti Bhatt. Chemotherapy-Induced CD70 Expression Enhances Anti-Tumor Immunity and CAR-T Cell Efficacy in Acute Myeloid Leukemia abstract. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86 (13Suppl): Abstract nr P03.
Wang et al. (Thu,) studied this question.