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PIM1/NF-κB/CCL2 blockade enhances anti-PD-1 therapy response by modulating macrophage infiltration and polarization in tumor microenvironment of NSCLC

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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 resha** 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.

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Fig. 1: Altering PIM1 levels within tumors influences macrophage chemotaxis and polarization in the TME.
Fig. 2: Regulation of tumor-infiltrating macrophages via PIM1 is dependent on CCL2 in tumors.
Fig. 3: Clinical correlation analysis of PIM1 and CCL2 in NSCLC samples.
Fig. 4: The role of PIM1 in chemotaxis and polarization of macrophages is mediated by CCL2.
Fig. 5: CCL2 expression in lung adenocarcinoma is regulated by PIM1 via the NF-κB pathway.
Fig. 6: PIM1-mediated p65 phosphorylation stimulates CCL2 secretion through promoter binding.
Fig. 7: Inhibition of Pim1 synergizes with PD-1 blockade to suppress tumor progression in a syngeneic mouse model.

Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Tian** Medical University Cancer Institute & Hospital for providing us with pathological specimens.

Funding

This present research was funded by the National Natural Science Foundation of China (No. 82172620 for Richeng Jiang and No. 82172635 for Dingzhi Huang).

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Author notes

  1. These authors contributed equally: **uqiong Chen, **g Zhou, Youhui Wang, **nyue Wang.

Authors and Affiliations

  1. Tian** Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention on and Therapy, Tian**’s Clinical Research Center for Cancer, Tian**, 300060, China

    **uqiong Chen, **g Zhou, Youhui Wang, **nyue Wang, Kaidi Chen, Qin Chen, Dingzhi Huang & Richeng Jiang

  2. Department of Thoracic Oncology, Tian** Lung Cancer Center, Tian** Cancer Institute and Hospital, Tian** Medical University, Tian**, 300060, China

    **uqiong Chen, **g Zhou, Youhui Wang, **nyue Wang, Kaidi Chen, Qin Chen, Dingzhi Huang & Richeng Jiang

  3. Department of Respiratory and Critical Medicine, Tian** Chest Hospital, Tian**, PR China

    Qin Chen

  4. Tian** Cancer Hospital Airport Hospital, National Clinical Research Center for Cancer, Tian**, 300000, China

    Richeng Jiang

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Contributions

Conceptualization: RCJ, DZH. Methodology: XQC, JZ, YHW, XYW, KDC, QC. Investigation: XQC, JZ, YHW. Acquisition of data: XQC, JZ, YHW, XYW. Visualization: XQC, XYW, KDC, QC. Funding acquisition: RCJ, DZH. Project administration: RCJ, DZH. Supervision: XYW, RCJ, DZH. Writing - original draft: XQC. Writing - review & editing or revision: XQC, JZ, YHW.

Corresponding authors

Correspondence to Dingzhi Huang or Richeng Jiang.

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The authors declare no competing interests.

Ethics approval

This research involving human subjects or human data received formal authorization from the Cancer Institute and Hospital Research Ethics Committee, following the World Medical Association’s Declaration of Helsinki guidelines (approval no.bc2023134). Informed consent was obtained from all participants after the nature and possible consequences of the studies were explained. All animal experiments were approved by the Institutional Animal Care and Use Committee of the Tian** Medical University Cancer Institute and Hospital (AE-2022026).

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Chen, X., Zhou, J., Wang, Y. et al. PIM1/NF-κB/CCL2 blockade enhances anti-PD-1 therapy response by modulating macrophage infiltration and polarization in tumor microenvironment of NSCLC. Oncogene (2024). https://doi.org/10.1038/s41388-024-03100-6

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