Aneuploidy—an aberration in the number of chromosomes—has been found to trigger a stress response in tumor cells that can initiate or amplify local immune cell dysregulation, promoting immune evasion. The idea that aneuploidy could promote immune evasion was first suggested several years ago. Back then, however, the mechanistic link between aneuploidy and immune evasion was still unknown.

To identify the link, scientists based at the University of California (UC), San Diego, School of Medicine and Moores Cancer Center at UC San Diego Health devised a unique aneuploidy score. Then they showed that it was inversely correlated with T-cell-mediated cytotoxicity across 9,375 tumors from the Cancer Genome Atlas (TCGA) database. They also noticed that as aneuploidy increases, there is a loss of coordination among the members of the unfolded protein response (UPR) pathway.

The scientists subjected the UPR pathway to additional scrutiny. They were curious to learn whether UPR in aneuploid cells could lead to the release of soluble molecules—molecules that could target neighboring cells and create a tumor-friendly microenvironment. Using an in vitro model, the scientists demonstrated that aneuploid cells release factors that polarize human macrophages to a pro-inflammatory/immune-suppressive phenotype and negatively regulate human T cells during activation.

Details of this work appeared October 26 in EMOB reports, in an article titled, “The unfolded protein response links tumor aneuploidy to local immune dysregulation.” The article describes the scientists’ aneuploidy score, which is a single somatic copy number alteration (SCNA) score inclusive of whole-chromosome, chromosome arm, and focal alterations. The article also indicates that co-expression patterns of UPR genes changed substantially between SCNAlow and SCNAhigh groups.

“Pathway activity scores showed increased activity of multiple branches of the UPR in response to aneuploidy,” the article’s authors wrote. “The PERK branch showed the strongest association with a reduced cytotoxicity score. The conditioned medium of aneuploid cells transmitted XBP1 splicing and caused IL-6 and arginase 1 transcription in receiver bone marrow-derived macrophages and markedly diminished the production of IFN-γ and granzyme B in activated human T cells.”

Aneuploidy has been shown to promote tumor development by increasing genetic diversity, instability, and evolution. Approximately 90% of solid tumors and half of blood cancers present some form of aneuploidy, which is associated with tumor progression and poor prognoses.

In recent years, it has become apparent that cells cohabiting within a tumor microenvironment are subject not only to external stressors (mainly of metabolic origin, such as lack of nutrients), but also to the internal stressor aneuploidy. Both activate UPR, which leads to an accumulation of misfolded proteins in the endoplasmic reticulum—an organelle that synthesizes proteins and transports them outside the cell.

When this primary transport/export system is disrupted, UPR attempts to restore normal function by halting the accumulation of misfolded proteins, by degrading and removing them, and by activating signaling pathways to promote proper protein folding.

If homeostasis or equilibrium is not reestablished quickly, nontumor cells undergo cell death. Conversely, cancer cells thrive in this chaos, establishing a higher tolerance threshold that favors their survival.

“In these circumstances, they also co-opt neighboring cells in a spiral of deceit that progressively impairs local immune cells,” said Maurizio Zanetti, MD, professor of medicine at UC San Diego School of Medicine, a tumor immunologist at Moores Cancer Center, and the senior author of the current study. (Zanetti had previously suggested a link between aneuploidy and immune dysregulation in a Science commentary, “Chromosomal chaos silences immune surveillance.”)

In the current study, Zanetti and colleagues sought to demonstrate that aneuploidy, UPR, and immune cell dysregulation can join together to form a deadly triangle. “This was an ambitious goal not attempted before,” Zanetti noted. “It was like interrogating three chief systems together—chromosomal abnormalities in toto, signaling mechanisms in response to endogenous stress, and dysregulation of neighboring immune cells—just to prove a bold hypothesis.”

The study demonstrated that the stress response in cancer cells serves as an unpredicted link between aneuploidy and immune cells to negatively regulate human T cells during activation. It also showed that molecules released by aneuploid cells affect macrophages, subverting their normal function and turning them into tumor-promoting actors.

The findings offer new opportunities to understand tumor progression as a balance between the progressive accumulation of chromosomal abnormalities during tumor evolution and the progressive decay of antitumor immunity, said the authors, with the signaling response to stress gauging and regulating the relationship.

In practical terms, they said, a new aneuploidy score defining the burden of chromosomal abnormalities, developed for the study, could set a new paradigm for assessing the biological stage of tumor progression in patients and be used to extrapolate immune status.

“It may also inform on new opportunities for pharmacological or genetic interventions that interfere with specific branches of the UPR as the mediator of aneuploidy-driven local immune dysregulation,” Zanetti suggested. “This non-immunological approach could make immunotherapy of cancer more efficient.”