The tumor microenvironment (TME) plays a crucial role in cancer progression, and it is highly complex with variations among different patients. In a recent research report published in the international journal Science titled “CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers,” scientists from institutions such as the Ludwig Cancer Research Center have identified a pair of genes that, when expressed in immune cells within tumors, may help predict the treatment outcomes of cancer patients. These genes are intricately connected to a vast network of gene expression programs involving multiple cell types within the tumor microenvironment, which collectively control the progression of human cancers.
Researchers believe that patients with high expression of the CXCL9 gene in tumor-associated macrophages fare better clinically compared to patients with high expression of the SPP1 gene in immune cells. Macrophages expressing the former gene are always prepared to attack cancer cells, while those expressing SPP1 are in a state that supports tumor growth. Interestingly, when the CXCL9-to-SPP1 ratio is high in the tumor microenvironment, other gene expression programs in various cells within the TME also exhibit a similar anti-tumor tendency. Conversely, lower CS ratios (CXCL9 to SPP1) are associated with pro-tumor gene expression characteristics throughout the entire tumor microenvironment.
Lead researcher Pittet stated, “We were surprised to find that just this one parameter—the ratio of two genes predominantly expressed in macrophages—can tell us a lot about the tumor and, as it turns out, across various types of solid tumors. This implies that, despite its complexity, the tumor microenvironment is governed by a set of specific rules, and this study describes one of them.” Researchers believe that with further validation through prospective clinical studies, the CS ratio could be an easily measurable molecular biomarker for predicting patient prognosis and serve as a useful tool for therapy management. The cross-cell type related gene expression features identified in this study may also reveal multiple potential molecular targets for the development of novel drugs that could push the tumor microenvironment into a highly susceptible state for therapies like immunotherapy.
Non-cancerous cells within the tumor microenvironment also play a crucial role in the growth and survival of tumors. These cells include fibroblasts that produce extracellular matrix components, endothelial cells that form blood vessels, epithelial cells lining body cavities, and various types of immune cells that can either aid or hinder tumor growth. Targeting these cells for cancer therapy is attractive because they tend to mutate less rapidly and are less likely to develop therapy resistance compared to malignant cells. Pittet and colleagues were particularly interested in understanding the extent of differences in the tumor microenvironment between different types of tumors. To find answers, they conducted an unbiased analysis of 52 primary and metastatic tumor samples from 51 patients with head and neck cancer, examining the overall gene expression within individual cells and conducting statistical analyses throughout the entire tumor to investigate its correlation with patient outcomes.
The researchers identified CXCL9 and SPP1 genes (whose expressions in single macrophages are mutually exclusive) closely associated with patient prognosis, and this was confirmed in other solid tumors as well. The relationship between the expression of these two genes and the anti-tumor and pro-tumor “polarity” of macrophages was clearer than currently used markers. Notably, the CXCL9-to-SPP1 expression ratio, known as CShi or CSlow, exhibited consistent patterns with the status of other types of tumor microenvironments in head and neck cancer and correlated with phenomena related to pro-tumor and anti-tumor effects. For instance, CShi tumors were more likely to be infiltrated by B cells, dendritic cells, and T lymphocytes, all of which drive anti-tumor immunity. Additionally, other cell types within these tumors also participated in signaling molecules and pathway transduction, inducing inflammation or triggering the body’s immune response. Meanwhile, CSlow tumors displayed gene expression characteristics associated with cancer growth and progression, such as adaptation to hypoxia, new blood vessel formation, and induction of cell transformation promoting cancer metastasis.
Pittet emphasized, “Simply by observing the ratio of these two genes in macrophages, we can infer the molecular activity of tumor cells, endothelial cells, and fibroblasts. This remarkable consistency suggests that the tumor is not a chaotic place, and all these cell states within the tumor microenvironment are coordinated. This information may be highly relevant for the development of individualized precision cancer therapies in the future.” In the next steps, researchers will analyze whether the gene expression network identified in this study can prospectively predict treatment outcomes for patients or measure their responses to various therapies. They will also delve deeper into other coordinated axes of gene expression within the tumor microenvironment and how they interact with and influence the CS ratio.
The biggest question remains: what is the best approach for therapeutic intervention in this network, and will it ultimately benefit patients? In conclusion, the results of this study indicate that, despite the complexity of the tumor microenvironment, it can coordinately control the coherent responses of human cancers, and the polarity of CS macrophages is a relevant yet straightforward variable.
Reference
1. Bill, Ruben, et al. “CXCL9: SPP1 macrophage polarity identifies a network of cellular programs that control human cancers.” Science 381.6657 (2023): 515-524.