Cancer is notorious for surrounding tumors with a hostile microenvironment in which tumors thrive, while the body’s immune forces are beaten back and robbed of their anti-cancer powers.
The tumor microenvironment – made up of blood vessels, inflammatory cells, and structural proteins – is something of a dense jungle that’s hard for cancer-killing immune T cells to penetrate. “It’s not Mister Rogers’ neighborhood,” says Laurie H. Glimcher, MD, an immunologist and President and CEO of Dana-Farber Cancer Institute.
Although the tumor microenvironment is known to be highly immunosuppressive, what hasn’t been clear is precisely how it specifically hampers the function of T cells, whose role is to detect and destroy cancer cells.
Reporting in Nature, scientists have identified a molecular pathway in T cells that is hijacked by the tumor microenvironment to disrupt T cell metabolism and function. Glimcher and collaborators at Weill Cornell Medicine have shown that ovarian cancer can sabotage T cells, triggering a molecular signaling pathway within the T cells that starves them of fuel for producing energy and weakens their anti-cancer functions.
This molecular signaling pathway, known as IRE1alpha-XBP1, is normally dormant, but becomes active when cells are under stress, as in cancer and other diseases. The researchers found that IRE1alpha-XBP1 was abnormally activated in T cells isolated from human ovarian cancers. The pathway was activated because T cells in that harsh environment were unable to take in glucose, which is necessary for protein folding and function. Chronic activation of IRE1alpha-XBP1 in this context instigated a stress response that prevented the T cells from using alternative energy sources like glutamine. Hence, the exhausted T cells failed to infiltrate tumors and produced less interferon gamma, which combats viruses and cancer.
“This is the first demonstration that this particular pathway reprograms metabolism in T cells, which are the key cells that fight tumors,” said Glimcher, the co-corresponding author of the Nature report with Juan R. Cubillos-Ruiz, PhD, of Weill Cornell Medicine. The first author is Minkyung Song, PhD, of Weill Cornell Medicine.
The study showed that when the pathway was experimentally shut down, the T cells regained their “metabolic fitness” and anti-tumor capabilities. This suggests, the scientists say, that drugs targeting the IRE1alpha-XBP1 pathway could represent a novel approach to cancer therapy.
The IRE1alpha-XBP1 pathway is a familiar culprit to Glimcher and Cubillos-Ruiz. They previously reported that the pathway is aberrantly activated and disrupts the metabolism of dendritic cells – another key type of immune cell – in the microenvironment of ovarian tumors. The IRE1alpha-XBP1 signaling pathway is an arm of the Unfolded Protein Response, which is triggered by a particular kind of stress: the abnormal accumulation of unfolded proteins in the endoplasmic reticulum (ER), which occurs in cancer, neurodegeneration, and metabolic dysfunction. Cancer cells exploit this pathway to adjust their protein-folding capacity and ensure survival under hostile tumor microenvironmental conditions.
“Our findings indicate that stress signals derived from the endoplasmic reticulum cause severe metabolic perturbations in T cells within the tumor, which facilitates malignant progression,” said Cubillos-Ruiz.
The scientists created mouse models of ovarian cancer including some that lacked XBP1 in their T cells, preventing the pathway from being activated. (Knocking out the pathway had no deleterious effect on the animals or their immune function.) In those animals, the T cells secreted more interferon gamma – the cancer-fighting substance; in addition, the tumors grew more slowly, and the mice survived longer than did the animals with intact XBP1.
Therefore, the authors wrote, “controlling endoplasmic reticulum stress or targeting IRE1alpha-XBP1 signaling may help restore T cell metabolic fitness and anti-tumor capacity in cancer hosts.”
The research was supported by the Irvington Institute Fellowship of the Cancer Research Institute (J.R.C-R.), the Ann Schreiber Mentored Investigator Award of the Ovarian Cancer Research Fund Alliance (J.R.C-R.), the Ovarian Cancer Academy-Early-Career Investigator Award W81XWH-16-1-0438 of the Department of Defense (J.R.C-R.), the Stand Up to Cancer Innovative Research Grant SU2C-AACR-IRG-03-16 (J.R.C-R.), the Jacquie Liggett Fellowship Award of Hearing the Ovarian Cancer Whisper (J.R.C-R.), Weill Cornell Medicine Funds (J.R.C-R. and L.H.G.), and NIH grant R01CA112663 (L.H.G.).