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Grant support

This study was supported by NIH grants to Y.L. and D.C.D., AECC (PROYE19040POST), Olga Torres Foundation, MICINN (SAF2017-84918-R cofinanced by the European Union Regional Fund), and Avon-Sau to A.P.

Analysis of institutional authors

Cuatrecasas MAuthorCortés MAuthorPostigo, ACorresponding Author

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May 31, 2021
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Article

Zeb1 induces immune checkpoints to form an immunosuppressive envelope around invading cancer cells

Publicated to:Science Advances. 7 (21): eabd7455- - 2021-05-01 7(21), DOI: 10.1126/sciadv.abd7455

Authors: Guo, Yan; Lu, Xiaoqin; Chen, Yao; Rendon, Beatriz; Mitchell, Robert A; Cuatrecasas, Miriam; Cortes, Marlies; Postigo, Antonio; Liu, Yongqing; Dean, Douglas C

Affiliations

IDIBAPS (August Pi i Sunyer Biomedical Research Institute), Barcelona, Spain - Author
Institució Catalana de Recerca i Estudis Avançats - Author
Shandong Provincial Qianfoshan Hospital - Author
Universitat de Barcelona - Author
University of Louisville Health Sciences Center - Author
Xiangya Hospital of Central-South University - Author
‎ Cent South Univ, Dept Ophthalmol, Xiangya Hosp, Changsha, Peoples R China - Author
‎ ICREA, Barcelona 08010, Spain - Author
‎ Shandong First Med Univ, Dept Hematol, Affiliated Hosp 1, Jinan 250014, Peoples R China - Author
‎ Univ Barcelona, Ctr Diagnost Biomed CDB, Dept Pathol, Hosp Clin, Barcelona 08036, Spain - Author
‎ Univ Barcelona, Dept Biomed, Barcelona 08036, Spain - Author
‎ Univ Barcelona, IDIBAPS, Grp Transcript Regulat Gene Express, Barcelona 08036, Spain - Author
‎ Univ Louisville, James Graham Brown Canc Ctr, Dept Med, Div Oncol,Hlth Sci Ctr, Louisville, KY 40202 USA - Author
‎ Univ Louisville, James Graham Brown Canc Ctr, Dept Surg, Hlth Sci Ctr, Louisville, KY 40202 USA - Author
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Abstract

The PDL1-PD1 immune checkpoint inhibits T cell activation, and its blockade is effective in a subset of patients. Studies are investigating how checkpoints are hijacked by cancer cells and why most patients remain resistant to immunotherapy. Epithelial mesenchymal transition (EMT), which drives tumor cell invasion via the Zeb1 transcription factor, is linked to immunotherapy resistance. In addition, M2-polarized tumor-associated macrophages (TAMs), which inhibit T cell migration and activation, may also cause immunotherapy resistance. How EMT in invading cancer cells is linked to therapy resistance and events driving TAM M2 polarization are therefore important questions. We show that Zeb1 links these two resistance pathways because it is required for PDL1 expression on invading lung cancer cells, and it also induces CD47 on these invading cells, which drives M2 polarization of adjacent TAMs. Resulting reprogramming of the microenvironment around invading cells shields them from the hostile inflammatory environment surrounding tumors.

Keywords

blockadelung-cancermacrophagesoriginpolarizationprogressionrastherapytranscription factorsBlockadeCell line, tumorCell movementEpithelial-mesenchymal transitionHumansImmune checkpoint proteinsImmunotherapyLung neoplasmsLung-cancerMacrophagesMesenchymal transitionOriginPolarizationProgressionRasTherapyTranscription factorsTumor microenvironmentZeb1 protein, humanZinc finger e-box-binding homeobox 1

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Science Advances due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2021, it was in position 7/74, thus managing to position itself as a Q1 (Primer Cuartil), in the category Multidisciplinary Sciences. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 2.95. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 2.62 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 15.37 (source consulted: Dimensions Jul 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-07-04, the following number of citations:

  • WoS: 57
  • Scopus: 54
  • Europe PMC: 45

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-07-04:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 49.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 49 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 4.2.
  • The number of mentions on the social network X (formerly Twitter): 6 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: China; United States of America.

the author responsible for correspondence tasks has been Postigo, Antonio.