Rajan Priyanka, Zollo Robert, Guo Yanqi, Alruwaili Mohammed, Zonneville Justin, Lieberman Mackenzie, Morreale Brian, James Caitlin, Long Mark, Olejniczak Scott H, Barbi Joseph, Abrams Scott I, Bakin Andrei V
bioRxiv. 2025 May 10:2025.05.08.652949. doi: 10.1101/2025.05.08.652949.
Metastatic breast cancer (MBC) is a life-threatening disease with limited therapeutic options. The immune suppressive tumor microenvironment (TME) limits the potency of the antitumor immune response and facilitates disease progression and metastasis. Our current study demonstrates that p38α is a druggable target in the TME that regulates the outcome of the immune-tumor interaction. The study revealed that systemic blockade of p38α reduces metastasis, and this anti-metastatic response is negated by depletion of CD8 T cells. Single-cell transcriptomic analysis of the immune-TME showed that pharmacological p38 inhibition (p38i) or tumor-specific inactivation of p38α by CRISPR/Cas9 (p38KO) resulted in a less exhausted and more activated CD8 T cell phenotype. Immunophenotyping analyses demonstrated that p38 blockade reduced the expression of multiple inhibitory receptors on CD8 T cells (i.e., PD-1, LAG-3, CTLA-4), indicating a reversal of immune exhaustion and enhanced immune activation systemically and in the TME. In contrast, p38 blockade did not exhibit inhibitory effects on T cells in proliferation assays and did not affect the proportion of regulatory T cells . The major negative impact of p38 blockade was on the myeloid populations, such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Further, tumor p38α activity was required for the expression of cytokines/chemokines and tumor-derived exosomes with high chemotactic capacity for myeloid cells. Altogether, this study highlights a previously unrecognized p38α-driven pathway that promotes an immune suppressive TME and metastasis, and that therapeutic blockade of p38α has important implications for improving antitumor immunity and patient outcomes.
This study highlights a previously unrecognized p38α-driven tumor pathway that promotes an immune suppressive microenvironment and metastasis, and that therapeutic blockade of p38α has important implications for improving antitumor immunity and patient outcomes.
转移性乳腺癌（MBC）是一种危及生命的疾病，治疗选择有限。免疫抑制性肿瘤微环境（TME）限制了抗肿瘤免疫反应的效力，并促进疾病进展和转移。我们目前的研究表明，p38α是TME中一个可药物靶向的靶点，它调节免疫-肿瘤相互作用的结果。该研究显示，p38α的全身阻断可减少转移，而这种抗转移反应会因CD8⁺ T细胞的耗竭而被消除。对免疫-TME的单细胞转录组分析表明，药理学上的p38抑制（p38i）或通过CRISPR/Cas9对p38α进行肿瘤特异性失活（p38KO）会导致CD8⁺ T细胞表型的耗竭减少且活化增加。免疫表型分析表明，p38阻断降低了CD8⁺ T细胞上多种抑制性受体的表达（即PD-1、LAG-3、CTLA-4），表明全身和TME中免疫耗竭的逆转以及免疫激活的增强。相比之下，p38阻断在增殖试验中对T细胞没有抑制作用，也不影响调节性T细胞的比例。p38阻断的主要负面影响在于髓系细胞群体，如髓系来源的抑制细胞（MDSCs）和肿瘤相关巨噬细胞（TAMs）。此外，肿瘤p38α活性对于具有高趋化能力的髓系细胞的细胞因子/趋化因子和肿瘤来源外泌体的表达是必需的。总之，本研究突出了一条先前未被认识的由p38α驱动的促进免疫抑制性TME和转移的途径，并且p38α的治疗性阻断对于改善抗肿瘤免疫和患者预后具有重要意义。
本研究突出了一条先前未被认识的由p38α驱动的促进免疫抑制性微环境和转移的肿瘤途径，并且p38α 的治疗性阻断对于改善抗肿瘤免疫和患者预后具有重要意义。
