Tumors Reprogram Neutrophils to Promote Blood Vessel Formation

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Tumors Reprogram Neutrophils to Promote Blood Vessel Formation

Tumors Reprogram Neutrophils to Promote Blood Vessel Formation

Scientists have made a groundbreaking discovery that tumors can extend the lifespan of neutrophils by three times, turning them into a “long-term worker” that promotes blood vessel formation.

In the face of solid tumors, immune cells always seem to be the weaker side.

In August of last year, researchers from Vanderbilt University in the United States found that cytotoxic T cells could undergo depletion within 6-12 hours after contact with tumors.

At the end of last year, a study from the Weizmann Institute of Science in Israel indicated that natural killer (NK) cells lose their anti-tumor activity within 24 hours of entering the tumor, and macrophages are turned against the tumor within 48 hours, playing a role in promoting tumor growth.

Recently, a research team led by Melissa S.F. Ng from the Agency for Science, Technology, and Research (A*STAR) in Singapore and Lai Guan Ng from A*STAR and Renji Hospital, Shanghai Jiao Tong University School of Medicine, published a groundbreaking research result in the top journal “Science,” elaborating on the fate of neutrophils inside tumors.

They discovered for the first time that neutrophils, upon entering the tumor, are reprogrammed by the tumor within a day to become a super-longevity pro-cancer subtype. Specifically, under the tutelage of the tumor, the lifespan of these neutrophils exceeds four times that of circulating neutrophils. Moreover, they are not afraid of low oxygen and nutrient-deprived environments, gathering near the tumor’s core area, expressing high levels of vascular endothelial growth factor alpha (VEGFα), promoting the formation of blood vessels in the tumor’s core area, providing nutrients to the tumor, and promoting tumor growth.

Melissa S.F. Ng, Immanuel Kwok, and Leonard Tan from A*STAR, along with Shichang Ming from Renji Hospital, Shanghai Jiao Tong University School of Medicine, are the co-first authors of the research paper.

Tumors Reprogram Neutrophils to Promote Blood Vessel Formation

As one of the most active and powerful immune cells, neutrophils always rush to the “scene of the crime” at the first opportunity.

However, in cancer, scientists have long observed that infiltrating neutrophils in tumors are associated with poor patient prognosis. It is even considered a type of immune cell that promotes cancer progression. However, scientists still know little about why neutrophils promote tumor progression.

To understand why neutrophils promote tumor progression and how they do it, the team led by Lai Guan Ng used pancreatic cancer as a research model. They employed single-cell transcriptomics and multi-omics methods with spatial resolution to delve into the changes, distribution, and functions of neutrophils in pancreatic cancer.

From the results of single-cell RNA sequencing (scRNAseq), in the tissues of neutrophil development and circulation, there is a single trajectory of change. Neutrophils in tumor tissues, however, are different; they acquire a unique transcriptional profile and form three different subtypes (T1, T2, and T3).

From the transcriptome features, the maturity of T1 neutrophils is equivalent to immature neutrophils, while the maturity of T2 neutrophils is comparable to mature neutrophils. Moreover, T1 and T2 neutrophils develop along a tumor-specific branch and converge towards the T3 subtype with maturity between T1 and T2. This implies that the T3 subtype may represent the terminal stage of differentiation from T1 and T2.

It is worth noting that transcriptomic data also show that in T3 neutrophils, the expression of genes related to hypoxia, glycolysis, and angiogenesis (such as Vegfa and Hk2, etc.) is upregulated, and chromatin accessibility increases. Neutrophils in other tissues do not exhibit these transcriptomic features.

Based on these research findings, the researchers believe that infiltrating neutrophils in tumors, regardless of their maturity stage, can be reprogrammed by the tumor microenvironment, and the trajectory of transcription and chromatin development tends towards the unique T3 state.

Next, Lai Guan Ng’s team evaluated whether these three subtypes could be distinguished by protein expression. The results revealed that only two proteins, CD101 and dcTRAIL-R1, were needed. CD101-positive neutrophils belonged to mature neutrophils, CD101-negative belonged to immature neutrophils, and the immune modulatory or inhibitory marker dcTRAIL-R1 symbolized T3 neutrophils. Thus, T1 neutrophils are CD101 and dcTRAIL-R1 double-negative, T2 is CD101 positive and dcTRAIL-R1 negative.

After understanding the characteristics of intratumoral neutrophils, it was necessary to understand their distribution and functions.

From the earlier transcriptomic data, T3 neutrophils exhibited clear features of cell stress and survival pathways, including responses to hypoxia, oxidative stress, and glycolysis. In addition, T3 neutrophils also enriched genes related to angiogenesis, including Vegfa, Thbs1, and Lgals3. The team believes that these data indicate that T3 not only adapts to the tumor environment but also has a strong pro-tumor effect.

From spatial transcriptomic data, compared to T1 and T2, T3 neutrophils appeared more frequently in high zones of glycolysis, hypoxia, and angiogenesis (the necrotic area of the tumor core, which is also the area where the tumor most needs nutrients).

Combining the initial transcriptomic data, it became clear why tumors position T3 neutrophils in the core region.

Tumors manipulate “blackened” neutrophils to promote the growth of blood vessels in the core region, delivering oxygen and nutrients to the depths of the tumor, thereby promoting tumor growth.

Co-injection experiments confirmed the conclusions drawn from transcriptomic data. Compared to T1 and T2, injecting T3 together with cancer cells into mice more effectively promoted blood vessel growth in tumors. In other words, T3 neutrophils had the strongest ability to promote angiogenesis.

When examining the timeline of the “blackening” of neutrophils by tumors, Lai Guan Ng’s team discovered that T3 reprogramming began upon entering the tumor. Moreover, they found that the lifespan of neutrophils after entering the tumor could be as long as 135 hours (almost 6 days), more than four times the half-life of neutrophils in the bloodstream (31 hours). Importantly, once neutrophils were reprogrammed into T3 neutrophils, even if they escaped the tumor, they would not revert to their original phenotype.

In summary, after neutrophils enter the tumor, the tumor begins to reprogram them. The expression of dcTRAIL-R1 gradually increases, and they develop towards the T3 type. Once transformed into super-longevity T3 neutrophils, tumors arrange them in the highly hypoxic core region, allowing T3 to induce the growth of blood vessels in the core region, thereby promoting tumor growth.

At the end of the study, Lai Guan Ng’s team explored the widespread existence of T3 neutrophils and their clinical application value.

They found that the reprogramming of tumor neutrophils is consistent across different tumor types, and T3 neutrophils represent the terminal differentiation state of tumor neutrophils.

Based on data from two independent pancreatic cancer cohorts, the Cancer Genome Atlas (TCGA) and

the Pancreatic Cancer – Australia (PACA-AU) from the International Cancer Genome Consortium, they also found that patients with high expression of T3 neutrophil characteristics had a worse overall survival period (OS), unaffected by potential confounding factors such as patient gender, age, and tumor stage.

Furthermore, in various other cancer types, high expression of T3 neutrophil characteristics was also associated with an increased risk of patient death.

In conclusion, this study led by Lai Guan Ng and Melissa S.F. Ng systematically explored the “blackening” process of neutrophils in tumors. They found that whether mature or immature neutrophils, once they enter the tumor, they are reprogrammed into T3 terminal neutrophils and then gather in the hypoxic and highly glycolytic core area of the tumor, promoting angiogenesis and supporting tumor growth.

This discovery deepens our understanding of the pro-tumor role of neutrophils, providing new insights for the development of immunotherapies targeting neutrophils.

Tumors Reprogram Neutrophils to Promote Blood Vessel Formation

References:

[1].Rudloff MW, Zumbo P, Favret NR, et al. Hallmarks of CD8+ T cell dysfunction are established within hours of tumor antigen encounter before cell division. Nat Immunol. 2023;24(9):1527-1539. doi:10.1038/s41590-023-01578-y

[2].Kirschenbaum D, Xie K, Ingelfinger F, et al. Time-resolved single-cell transcriptomics defines immune trajectories in glioblastoma. Cell. doi:10.1016/j.cell.2023.11.032

[3].Ng MSF, Kwok I, Tan L, et al. Deterministic reprogramming of neutrophils within tumors. Science. 2024;383(6679):eadf6493. doi:10.1126/science.adf6493

[4].Gentles AJ, Newman AM, Liu CL, et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med. 2015;21(8):938-945. doi:10.1038/nm.3909

[5].Bronte V, Brandau S, Chen SH, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016;7:12150. doi:10.1038/ncomms12150

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