Abstract 5255: Systemic immunosuppression in pancreatic cancer

Background: Natural killer (NK) cells play a critical role in cancer immunosurveillance and are considered a potent immunotherapeutic tool for many cancers, including pancreatic ductal adenocarcinomas (PDACs). Increased number of ongoing clinical trials investigating CAR-T/NK cell therapies in PDAC patients (NCT04390399, NCT02839954, NCT03634501, NCT03941457, NCT03323944, NCT05275062) driving the need for research understanding of how systemic immune perturbations regulate the effector function of adoptively transferred immune cells is important for development of these therapies. The immunosuppressive tumor microenvironment contributes to shaping antitumor immunity and can dramatically diminish the efficacy of immunotherapies. However, the effects of PDAC tumor burden on systemic NK cells remain poorly understood. Emerging evidence suggests that cancer can induce systemic immune perturbations, including an increase in immunosuppressive myeloid populations in lymphoid organs. Understanding the interplay between these systemic factors and local anti-tumor immunity is crucial for developing effective immunotherapies against PDAC. Methods: To investigate the systemic effects of PDAC on the NKs, we orthotopically implanted immunocompetent C57BL/6 mice with syngeneic pancreatic tumor cell lines derived from LSL-KrasLSL.G12D/+; LSL-p53R172H/+; Pdx1-Cre (KPC mice) PDAC mouse model. Next, we evaluated the functional, transcriptional, and metabolic profiles of endogenous and adoptively transferred syngeneic NK cells. Results: Our study showed remarkable impairment in the effector function of endogenous and adoptively transferred NKs obtained from tumor-bearing mice compared to the healthy mice. Endogenous and adoptively transferred NK cells displayed attenuated cytotoxic killing capabilities against pancreatic tumor cells in the ex vivo assay. Besides, our metabolomics data demon stared an altered metabolism in the NK cells from the pancreatic tumor mice compared to healthy control cohort. Depleting myeloid cells rescued the proportion and cytotoxic function of systemic NK cells in pancreatic tumor-bearing mice. Also, myeloid cells alter the metabolism of NK cells, which underlie the attenuated cytotoxic function of these cells in pancreatic cancer. Conclusion: Our study proves the critical role of the systemic immunosuppressive in impairing the function of endogenous and adoptively transferred NK cells in pancreatic cancer. We demonstrate that inhibiting myeloid cells enhances the anti-tumor function of NK cells. Our findings also show the importance of considering the systemic immune microenvironment in cancer patients when utilizing CAR T/NK-based therapies. Citation Format: Damian Matysniak, Chunbo He, Pankaj Kumar Singh, Kamiya Mehla. Systemic immunosuppression in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5255.