Science Advances has recently published a research article discussing how the PDL1-PD1 immune checkpoint inhibits T cell activation. Checkpoint immunotherapy is known to be a revolutionizing treatment for previously refractive tumors. However, researchers had found that only a portion of patients responded, and some responders gained resistance. In the article, researchers were inspecting how checkpoints were hijacked by cancer cells and why most patients were remaining resistant to immunotherapy. Multiple factors linked to resistance are being found.



M2-polarized tumor-associated macrophages (TAMs) 

In the article, researchers identified M2-polarized tumor-associated macrophages (TAMs) as one of the resistance factors secreting immunosuppressive cytokines to inhibit T cell recruitment and activation. There is a question under researchers’ examination on how TAMs become alternatively polarized in cancer.

Epithelial mesenchymal transition (EMT)

The second factor on immunotherapy resistance forecasted by researchers was epithelial mesenchymal transition (EMT). In the article, researchers reported that, as EMT is associated with cancer cell invasion, its role in immunotherapy resistance would be targeted at the stage of cancer cell invasion and seemingly on the invading cells. Researchers are unclear whether these two supposedly disparate resistance factors might be related.

Zeb1 transcription factor

The article demonstrated that Zeb1 is linked with these two resistance pathways as it required PDL1 expression on invading lung cancer cells. At the same time, it is reported that Zeb1 can also induce CD47 on these invading cells, which makes M2 polarization of adjacent TAMs. The resulting reprogramming of the microenvironment around invading cells safeguarded them from the unfavorable inflammatory environment surrounding tumors, as stated in the article.





The article concludes, invading cancer cells are targets of immune checkpoint therapy. Because Zeb1 induces these checkpoints, its expression in these invading cells might anticipate patient response to immunotherapy.


The full article of Science Advances is available here: https://advances.sciencemag.org/content/advances/7/21/eabd7455.full.pdf


Yongqing Liu, Douglas C. Dean, Yan Guo, Xiaoqin Lu, Yao Chen, Beatriz Rendon, Robert A. Mitchell, Miriam Cuatrecasas, Marlies Cortés, Antonio Postigo. Zeb1 induces immune checkpoints to form an immunosuppressive envelope around invading cancer cells. Science Advances. 2021 May 21; 7(21). DOI: 10.1126/sciadv.abd7455.

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