Scientists discover differences in the interaction of T cells in tumor microenvironments


A team led by Northwestern Medicine researchers found differences in the distribution and interaction of T cells in the microenvironment of different regions of brain tumors and brain metastases, according to findings published in the journal JCI Overview. The results demonstrate how the immune cell interactome is distinct between cancer lineages.

These interactions likely influence how we intrinsically generate immune responses to cancer. »


Amy Heimberger, MD, Jean Malnati Miller Professor of Brain Tumor Research and lead study author

Amy Heimberger, MD, Jean Malnati Miller Professor of Brain Tumor Research and lead author of the study published in JCI Insight.

The body’s immune system responds to brain tumors through lymphatic drainage of tumor antigens, in which dendritic cells, or antigen-presenting immune cells, present tumor antigens in the lymph nodes to T cells, which are then activated. These T cells then travel to the tumor microenvironment where they are involved in the destruction of tumor cells.

Previous studies have shown that trafficking to the tumor microenvironment depletes T cells in cancers that reside in the brain, rendering them less effective or even inactive once they reach the tumor. According to Heimberger, some of these cluster interactions may indicate an advantage in initiating T cell activation before T cell depletion.

In the current study, Heimberger’s team aimed to determine the degree to which T cells are distributed and interact in different regions of brain tumors, including regions of cell death or necrosis and at the edge of infiltration, or where healthy brain tissue and tumor meet. .

Compared to recent studies that explored the tumor microenvironment and its immune composition through tumor biopsies, Heimberger’s team used in block resections of gliomatous tumors and lung cancer cerebral metastases. Unlike a traditional biopsy, these resections preserve tissue structure, orientation and architecture in all areas of the tumor microenvironment.

“We analyzed these cellular interactions in linearity and continuity within the tumor microenvironment. The tumor microenvironment is not just the tumor, but also the edge and necrosis of the tumor,” said Hinda Najem, MD, MS, postdoctoral fellow at the Heimberger lab and lead author. of the study. “Because we looked at the tissue in continuity, we could see that tumors in the brain create a gradient of macrophages in the adjacent brain.”

Infiltration of CD3+ T cells shown at the level of the gliotic plane (infiltrating edge) in low-grade glioma. Courtesy of Jared Burks, PhD.

Using multiplex immunofluorescence staining and single-cell RNA sequencing, the team examined the distribution and interactions of T cells in primary and metastatic brain tumors, as well as the inferred functionality of these T cells in the tumor microenvironment.

Overall, researchers found marked differences in tumor microenvironments, cancer lineage, and cellular partners interacting with T cells. For example, in gliomas, T cells were localized to the infiltrating edge and l perivascular space of tumors, but in metastatic tumors, T cells have been found in the stroma, which holds the tumor tissues together. They also discovered that immunosuppressive cells that express the transcription factor STAT3 tend to clump together.

“This research highlights the fact that when tumors metastasize, they seek out locations enriched by the negative influences of CD163+ macrophages. We need to find ways to rearrange cells to sequester these immunosuppressive cells from our tumor microenvironments or we need them reprogram to be less immunosuppressive,” said Jared Burks, PhD, co-director of the Flow Cytometry & Cell Imaging Core Facility at the University of Texas MD Anderson Cancer Center and co-author of the study.

The study also lays the groundwork for assessing the role of newly defined immune cell populations in brain tumor growth and therapeutic responses.

Hinda Najem, MD, MS, postdoctoral fellow at the Heimberger Laboratory and lead author of the study.

“Therapeutics are currently very focused on targeting individual cells. A future area of ​​therapeutics could be envisioned to specifically modulate relationships between cells,” Heimberger said.

Source:

Journal reference:

Najem, H. et al. (2022) The central nervous system immune interactome is a function of cancer lineage, tumor microenvironment, and STAT3 expression. JCI Overview. doi.org/10.1172/jci.insight.157612.

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