open access publication

Article, 2024

CKLF instigates a “cold” microenvironment to promote MYCN-mediated tumor aggressiveness

Science Advances, ISSN 2375-2548, Volume 10, 11, Page eadh9547, 10.1126/sciadv.adh9547

Contributors

Qin, Xiaodan [1] Lam, Andrew [1] Zhang, Xu 0000-0002-8007-2762 [1] [2] Sengupta, Satyaki [3] [4] Iorgulescu, Julian Bryan 0000-0003-1405-3667 [3] [4] [5] Ni, Hongru [1] Das, Sanjukta 0000-0003-1339-8487 [3] [4] [6] Rager, Madison 0009-0006-0350-6009 [1] Zhou, Zhenwei 0000-0002-9424-7826 [1] Zuo, Tao 0000-0002-2125-7548 [7] Meara, Grace K 0009-0008-9201-2688 [1] Floru, Alexander E. [1] Kemet, Chinyere [1] Veerapaneni, Divya 0000-0002-5082-9752 [1] Kashy, Daniel 0000-0003-3276-8666 [1] Lin, Liang [3] [4] Lloyd, Kenneth 0000-0003-2343-2255 [8] Kwok, Lauren [1] Smith, Kaylee S. [1] Nagaraju, Raghavendar Thyagaraja 0000-0002-6891-5181 [9] [10] Meijers, Rob 0000-0003-2872-6279 [8] Ceol, Craig Joseph [11] Liu, Ching-Ti [1] Alexandrescu, Sanda [3] [12] Wu, Catherine J. [3] [4] [13] Keskin, Derin Benerci 0000-0002-8496-6181 [1] [3] [4] [14] [15] George, Rani E [3] [4] Feng, Hui 0000-0003-1318-821X (Corresponding author) [1]

Affiliations

  1. [1] Boston University
    2. [NORA names: United States; America, North; OECD];
  2. [2] South China Agricultural University
    3. [NORA names: China; Asia, East];
  3. [3] Harvard University
    4. [NORA names: United States; America, North; OECD];
  4. [4] Dana-Farber Cancer Institute
    5. [NORA names: United States; America, North; OECD];
  5. [5] The University of Texas MD Anderson Cancer Center
    6. [NORA names: United States; America, North; OECD];

Abstract

Solid tumors, especially those with aberrant MYCN activation, often harbor an immunosuppressive microenvironment to fuel malignant growth and trigger treatment resistance. Despite this knowledge, there are no effective strategies to tackle this problem. We found that chemokine-like factor (CKLF) is highly expressed by various solid tumor cells and transcriptionally up-regulated by MYCN. Using the MYCN-driven high-risk neuroblastoma as a model system, we demonstrated that as early as the premalignant stage, tumor cells secrete CKLF to attract CCR4-expressing CD4+ cells, inducing immunosuppression and tumor aggression. Genetic depletion of CD4+ T regulatory cells abolishes the immunorestrictive and protumorigenic effects of CKLF. Our work supports that disrupting CKLF-mediated cross-talk between tumor and CD4+ suppressor cells represents a promising immunotherapeutic approach to battling MYCN-driven tumors.

Keywords

CD4<sup>+</sup> T regulatory cells, CD4<sup>+</sup> cells, CKLF, MYCN, MYCN activation, MYCN-driven tumors, T regulatory cells, activity, aggression, approach, cells, chemokine-like factor, cross-talk, factors, genetic depletion, growth, high-risk neuroblastoma, immunosuppression, immunosuppressive microenvironment, immunotherapeutic approaches, knowledge, malignant growth, microenvironment, model, model system, neuroblastoma, premalignant stage, problem, protumorigenic effects, resistance, solid tumor cells, solid tumors, stage, suppressor cells, system, transcription, transcriptional up-regulation, treatment resistance, tumor, tumor aggressiveness, tumor cells

Funders

  • National Cancer Institute
  • China Scholarship Council
  • American Cancer Society
  • Alex's Lemonade Stand Foundation
  • Congressionally Directed Medical Research Programs
  • St. Baldrick's Foundation
  • Directorate for Engineering
  • Conquer Cancer Foundation
  • National Heart Lung and Blood Institute

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