A Ludwig Cancer Research study has identified a pair of genes whose expression by a variety of immune cell inside tumors is predictive of outcomes for cancer patients and is linked to an unlimited network of gene expression programs, engaged by multiple cell types within the tumor microenvironment, that control human cancers.

Researchers led by Ludwig Lausanne’s Mikaël Pittet report in the present issue of Science that patients with higher expression of the gene CXCL9 of their tumor-associated macrophages had much better clinical outcomes than those with higher expression of a gene named SPP1 by the immune cells. Macrophages expressing the previous gene, they show, are invariably poised to attack cancer cells, while those expressing SPP1 are in a state supportive of tumor growth. Most intriguing, nonetheless, is the invention that when the ratio of CXCL9 to SPP1 is high within the tumor microenvironment (TME), gene expression programs in other TME cells indicate a similarly anti-tumor slant; a low CS ratio, then again, invariably accompanies pro-tumor gene expression signatures across the TME.

We were very surprised to search out that just this one parameter-;the ratio of two genes primarily expressed by macrophages-;could tell us a lot else concerning the tumor. That is true for multiple forms of solid tumors. It implies that, despite their enormous complexity, the microenvironments of tumors are governed by a transparent algorithm. Now we have described considered one of them on this study.”

Ludwig Lausanne’s Mikaël Pittet

With further validation in prospective clinical studies, Pittet noted, the CS ratio might be an easily measured molecular marker of likely patient prognosis and a great tool for the management of therapy. Beyond that, the networks of linked gene expression signatures across cell types identified by the study expose several potential molecular targets for the event of medicine that may tip the TME right into a state more vulnerable to treatments like immunotherapy.

Noncancerous cells of the TME play a critical role in the expansion and viability of tumors. These include fibroblasts, which churn out the molecular filler of tissues, endothelial cells that construct blood vessels, epithelial cells that line body cavities and a menagerie of immune cell species that variously help or hinder tumor growth. The potential of targeting these cells to treat cancers is tantalizing because, unlike malignant cells, they don’t mutate rapidly and are thus unlikely to evolve resistance to therapies.

Pittet and his colleagues were enthusiastic about how much the TME varies between tumors. To seek out out, they conducted an unbiased evaluation of 52 primary and metastatic tumors from 51 patients with head and neck cancers, examining how global gene expression captured in individual cells but statistically analyzed across tumors as a complete corresponded to patient outcomes.

This approach identified CXCL9 and SPP1-;whose expression is mutually exclusive in individual macrophages-;as being tightly linked to prognosis, and this turned out to be true for other solid cancers as well. The expression of the 2 genes, Pittet and colleagues show, can be more categorically related to the anti-tumor or pro-tumor “polarity” of macrophages than currently used markers.

Notably, the ratio of CXCL9 and SPP1 expression (termed CShi or CSlow) was broadly consistent with the state of other forms of TME cells in head and neck tumors and with several phenomena related to pro- and anti-tumor effects. CShi tumors, for instance, tended to be infiltrated with B and T lymphocytes and dendritic cells, which all drive anti-tumor immunity. Further, other cell types in these tumors engaged signaling molecules and pathways that fuel inflammation or otherwise instigate immune responses.

CSlow tumors, meanwhile, bore gene expression signatures related to cancer growth and progression, akin to adaptations to oxygen starvation, the formation of latest blood vessels and the induction of cellular transformations that propel cancer metastasis.

“Just by taking a look at the ratio of those two genes in macrophages, you may deduce the molecular activity of tumor cells, endothelial cells, fibroblasts-;you name it,” said Pittet. “This startling coherence implies that tumors usually are not a chaotic place, that each one these cell states throughout the TME are coordinated. This information has the potential to be very useful for the event of precision medicine strategies for cancer therapy.”

Pittet and his colleagues will next examine whether the gene expression networks identified of their study could be used to prospectively predict patient outcomes or gauge likely responses to numerous therapies. They will even be looking in additional detail at other coordinated axes of gene expression within the TME, how they interact with the CS ratio and the way each influences the opposite.

“The large query is, what are the most effective ways to interfere therapeutically with this network, with the goal being profit to the patient?” said Pittet.

Source:

Ludwig Institute for Cancer Research

Journal reference:

Bill, R., et al. (2023) CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers. Science. doi.org/10.1126/science.ade2292.