Highlights in Cancer Research: March 2024

The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).

The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.

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2. Deterministic reprogramming of neutrophils within tumors

Ng M. S.F., Kwok, I., Tan, L., Shi, C. et al. Science. 383 (6679), eadf6493 (2024).
doi: doi.org/10.1126/science.adf6493.

Summary of the findings

Diverse neutrophils populations varying by maturation stages, surface marker expression and transcriptional profiles infiltrate the tumor and are associated with poorer patient outcomes in cancer. Yet, how these different neutrophil states are coordinated into a unified pro-tumoral neutrophil response remains undefined. Using a mouse model of orthotopic pancreatic cancer, Ng et al. demonstrate that neutrophils undergo further epigenetic and transcriptional reprogramming upon entry into the tumor. This mechanism thus ensures neutrophils of various tissue origins or maturation stages eventually converge into a long-lived population with potent pro-angiogenic function within the tumor. Residing at a unique hypoxic-glycolytic tumor niche, reprogrammed neutrophils are optimally located to promote angiogenesis in hypoxic and nutrient-poor tumor regions. Specifically, they expressed high levels of vascular endothelial growth factor alpha (VEGFα), which significantly enhanced blood vessel formation within the tumor core and accelerated tumor growth. Depleting reprogrammed neutrophils or blocking their angiogenic function then inhibits this growth enhancement effect. The presence of neutrophil reprogramming was also observed in human cancer, where the reprogrammed neutrophil signature was associated with reduced overall survival in pancreatic cancer and other solid tumors. This work highlights the untapped possibilities of targeting pro-tumoral neutrophil responses to enhance cancer immunotherapy.

Tumor-infiltrating neutrophils undergo convergent reprogramming into pro-angiogenic neutrophils that support tumor growth. In cancer, both immature and mature neutrophils infiltrate the tumor. After entering the tumor microenvironment, these neutrophils undergo differentiation, leading to the formation of transitional populations. Through reprogramming, these populations ultimately converge into a terminal neutrophil state. Reprogrammed neutrophils strongly express VEGFα and localize to a unique hypoxic-glycolytic niche near the tumor core. This places them in an optimal position to exert their pro-angiogenic function within hypoxic and nutrient- poor tumor regions, thereby promoting tumor growth. The emergence of tumor reprogramming reflects the adaptability of neutrophils to environmental cues, allowing them to consolidate their protumoral responses. From Melissa S. F. Ng et al., Deterministic reprogramming of neutrophils within tumors. Science 383, eadf6493(2024). DOI:10.1126/science.adf6493. Reprinted with permission from AAAS.

Neutrophils undergo reprogramming upon tumor entry, following a common path which unites their different functional states into a single pro-tumoral phenotype which can be specifically targeted. Importantly, this study provides evidence that this process is conserved in human solid tumors. This suggests that targeting reprogrammed neutrophils could be a new and viable therapeutic approach to inhibit angiogenesis and tumor growth in human cancer. Further studies facilitating the discovery of transcription factors, as well as tumor-derived factors, that mediate neutrophil reprogramming as well as their acquisition of pro-angiogenic function, represent important goals for the field to advance this process.