Abstract：
Elevated infiltration of tumor-associated macrophages (TAMs) drives tumor progression and correlates with poor prognosis for various tumor types. Our research identifies that the ablation of the Pim-1 proto-oncogene (PIM1) in non-small cell lung cancer (NSCLC) suppresses TAM infiltration and prevents them from polarizing toward the M2 phenotype, thereby reshaping the tumor immune microenvironment (TME). The predominant mechanism through which PIM1 exerts its impact on macrophage chemotaxis and polarization involves CC motif chemokine ligand 2 (CCL2). The expression level of PIM1 is positively correlated with high CCL2 expression in NSCLC, conferring a worse overall patient survival. Mechanistically, PIM1 deficiency facilitates the reprogramming of TAMs by targeting nuclear factor kappa beta (NF-κB) signaling and inhibits CCL2 transactivation by NSCLC cells. The decreased secretion of CCL2 impedes TAM accumulation and their polarization toward a pro-tumoral phenotype. Furthermore, Dual blockade of Pim1 and PD-1 collaboratively suppressed tumor growth, repolarized macrophages, and boosted the efficacy of anti-PD-1 antibody. Collectively, our findings elucidate the pivotal role of PIM1 in orchestrating TAMs within the TME of NSCLC and highlight the potential of PIM1 inhibition as a strategy for enhancing the efficacy of cancer immunotherapy.
摘要：
肿瘤相关巨噬细胞(TAM)的高度浸润驱动肿瘤进展并与各种肿瘤类型的不良预后相关。我们的研究发现，在非小细胞肺癌（NSCLC）中Pim-1原癌基因（PIM1）的消融抑制了TAM浸润，并防止它们向M2表型极化。从而重塑肿瘤免疫微环境(TME)。PIM1对巨噬细胞趋化和极化的影响的主要机制涉及CC基序趋化因子配体2(CCL2)。非小细胞肺癌组织中PIM1的表达水平与CCL2的高表达呈正相关。导致患者总体生存率下降。机械上,PIM1缺陷通过靶向核因子κβ（NF-κB）信号促进TAM的重编程，并抑制NSCLC细胞的CCL2反式激活。CCL2分泌的减少阻碍了TAM的积累及其向肿瘤前表型的极化。此外，Pim1和PD-1的双重阻断协同抑制肿瘤生长，重新极化的巨噬细胞，并提高了抗PD-1抗体的疗效。总的来说，我们的研究结果阐明了PIM1在NSCLCTME内协调TAM中的关键作用,并强调了PIM1抑制作为增强癌症免疫治疗疗效的策略的潜力.
