Abstract PO4-13-09: Paclitaxel affects the efficacy of PD-1 blockade by interfering with lipid metabolism reprogramming in patients with breast cancer

Abstract Background: The question of how chemotherapeutic drugs affect the efficacy of PD-1/PD-L1 antibodies in patients with breast cancer is still pending. In a previously single-cell sequencing study, we have demonstrated that paclitaxel reduces the level of CXCL13+ T cells and other immune cells critical for atezolizumab to work, leading to inferior efficacy of atezolizumab in triple negative breast cancer (TNBC). How paclitaxel affects these important immune cells remains obscure. Recently, plasma metabolomic and proteomics analysis have shown that patients’ systemic metabolic signatures is correlated with the response of PD-1/PD-L1 antibody. As such, understanding the differential metabolic influences of the diverse chemotherapeutic drugs that comprise an immune response to TNBC offers an opportunity to appropriately select chemotherapeutic backbones for ICIs. Methods: We collected pre- and post-treatment plasma samples from breast cancer patients for metabolomic and proteomic analysis, including four patient cohorts: two independent cohorts (discovery cohort and validation cohort) in which patients were treated with ICIs, one cohort in which patients were treated with paclitaxel, and one cohort of patients treated with nab-paclitaxel. Patients were divided into responder group (R, tumor shrinkage) or non-responder group (NR, tumor increase) according to the change in tumor size after treatment relative to baseline. This was followed by integrating metabolomics and proteomics with single-cell transcriptome, along with in vitro experiments, to shed light on the mechanisms of action leading to ICIs resistance in breast cancer patients. Results: In the discovery cohort, the metabolites that mostly differed between the R and NR groups at baseline were lysoglycerophospholipids. These results were further validated in the validation cohort of patients. The dynamic changes of lysoglycerophospholipids were still significantly different between the R and the NR groups after ICIs treatment in the discovery cohort. It’s worth noting that the level of lysophosphatidylcholines (LPCs), the most prominent lysoglycerophospholipids, increased significantly in the R group, while no significant changes among LPCs were found in the NR group after ICIs treatment. In the validation cohort, the median PFS of LPClow patients was 1.8 months versus 6.8 months in the LPChigh group (P = 0.0068). After one cycle of paclitaxel treatment, the metabolic status of patients changed dramatically, especially the levels of lipids. It is notable that most LPCs were significantly downregulated after paclitaxel treatment. However, in patients who received nab-paclitaxel, few significantly changed lipids were detected after one cycle nab-paclitaxel treatment compared with their baseline conditions. Interestingly, the levels of LPCs were upregulated after one cycle nab-paclitaxel treatment, but decreased after paclitaxel treatment. Single-cell omics results showed that in patients' PBMCs, CXCR4+ NK cells were the most closely related to plasma LPC levels, while FGFBP2+ NK cells were in the tumor microenvironment. We isolated and expanded NK cells from PBMCs for in vitro experiments, and found that LPC stimulation can significantly upregulate the expression of CXCR4+ in NK cells, and further increase the chemotaxis and cytotoxicity of NK cells. Conclusions: In breast cancer patients receiving ICIs, the systemic lipid metabolism status, especially lysoglycerophospholipids, is closely related to the efficacy of immunotherapy. The key molecule LPC, the most prominent lysoglycerophospholipids, may promote the efficacy of immunotherapy by activating NK cells in breast cancer patients. Paclitaxel may impair the efficacy of immunotherapy by affecting the systemic lipid metabolism status, especially by reducing plasma LPC levels, so it is not a suitable partner for ICIs. Citation Format: Hongnan Mo, Jiashu Han, Jingtong Zhai, Xiaoying Sun, Xiuwen Guan, Haili Qian, Fei Ma. Paclitaxel affects the efficacy of PD-1 blockade by interfering with lipid metabolism reprogramming in patients with 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 PO4-13-09.