Cancer Can Change Neutrophils’ Behavior Influencing Them to Support Tumor Growth

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Source: Immunity

Cells live in complex communities called microenvironments, where many different types of cells interact with one another. In cancer, the microenvironment is a place where cancer cells and healthy cells interact. Oliver's study outlines a lung tumors' influence on immune cells in its microenvironment. Represented in illustration A is a lung tumor. The lung tumor's microenvironment includes many types of healthy cells and cancer cells, in illustration B. Within this microenvironment, lung cancer cells influence immune cells to develop behaviors that support the cancer cell as reflected in illustration C. [Trudy Oliver Lab]
Cells live in complex communities called microenvironments, where many different types of cells interact with one another. In cancer, the microenvironment is a place where cancer cells and healthy cells interact. Oliver’s study outlines a lung tumors’ influence on immune cells in its microenvironment. Represented in illustration A is a lung tumor. The lung tumor’s microenvironment includes many types of healthy cells and cancer cells, in illustration B. Within this microenvironment, lung cancer cells influence immune cells to develop behaviors that support the cancer cell as reflected in illustration C. [Trudy Oliver Lab]


Scientists at the Huntsman Cancer Institute (HCI) at the University of Utah (U of U) say they have gained new insights into the microenvironment surrounding different types of lung tumors and how these complex cell ecosystems may in turn ultimately affect response to treatment. Their study (“The Lineage-Defining Transcription Factors SOX2 and NKX2-1 Determine Lung Cancer Cell Fate and Shape the Tumor Immune Microenvironment”) appears in the journal Immunity.


“The major types of non-small-cell lung cancer (NSCLC)—squamous cell carcinoma and adenocarcinoma—have distinct immune microenvironments. We developed a genetic model of squamous NSCLC on the basis of overexpression of the transcription factor Sox2, which specifies lung basal cell fate, and loss of the tumor suppressor Lkb1 (SL mice). SL tumors recapitulated gene-expression and immune-infiltrate features of human squamous NSCLC; such features included enrichment of tumor-associated neutrophils (TANs) and decreased expression of NKX2-1, a transcriptional regulator that specifies alveolar cell fate. In Kras-driven adenocarcinomas, mis-expression of Sox2 or loss of Nkx2-1 led to TAN recruitment,” write the investigators.


“TAN recruitment involved SOX2-mediated production of the chemokine CXCL5. Deletion of Nkx2-1 in SL mice (SNL) revealed that NKX2-1 suppresses SOX2-driven squamous tumorigenesis by repressing adeno-to-squamous transdifferentiation. Depletion of TANs in SNL mice reduced squamous tumors, suggesting that TANs foster squamous cell fate. Thus, lineage-defining transcription factors determine the tumor immune microenvironment, which in turn might impact the nature of the tumor.”


“We sought to figure out why the immune microenvironment of lung cancer types was different,” says Trudy Oliver, Ph.D., HCI cancer researcher and associate professor of oncological sciences at the U of U, who oversaw the study. “We know that different kinds of tumor cells interact with different kinds of immune cells, and these immune cells have functions that can help or hurt the tumor. Essentially, tumors get these immune cells to do their dirty work for them. We noticed in both mice and in people that some tumors clinically thought of under the same umbrella are distinct in many ways that were not previously understood. Most strikingly, different lung tumor types were recruiting different types of immune cells.” 


Using a mouse model developed by her lab, along with sophisticated single-cell sequencing technology, Dr. Oliver's work uncovered clues to the role neutrophils play in different types of lung cancer. In humans and other organisms, neutrophils are the body's first responders to an injury. Neutrophils are present at sites of trauma such as a cut, and they are part of the body's innate response to fighting a tumor. It had been previously shown that poor prognosis in lung cancer and poor response to immunotherapy treatment for lung cancer were associated with high levels of neutrophils. 


“The association of a high presence of neutrophils with a bad response to immunotherapy means neutrophils might be a target for scientists to develop new treatments to help people who aren't responding well to currently available drugs,” Dr. Oliver suggests. She found that the tumors changed the behavior of the neutrophils, causing inhibition of their normal roles and influencing them to behave in ways that supported tumor growth. 


Gurkan Mollaoglu, a Ph.D. student in Dr. Oliver's lab, conducted the laboratory work. “It is both challenging and exciting to study how cancer cells shape their environment to become more favorable for the cancer,” says Mollaoglu. “The mouse models that we developed here are powerful tools that mirror many features of human tumors. Using these models, we showed how cancer cells modify their microenvironment and how the altered microenvironment, in return, favors cancer cells.” 


In the next steps of the work, Dr. Oliver and her team plan to characterize what the neutrophils do to help the tumors, and whether altering neutrophils can improve response to lung cancer therapies.








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