Researchers from the University of Geneva (UNIGE) and the Ludwig Institute for Cancer Research have identified a specific subpopulation of tumor-associated neutrophils (TANs), characterized by high expression of the chemokine CCL3, that actively promotes tumor growth and survival across various cancer types. The findings were published in the journal Cancer Cell.
The study outlines the genetic program and molecular mechanisms by which these CCL3hi neutrophils contribute to cancer progression, suggesting they could serve as a prognostic biomarker and a target for cancer therapies.
Discovery and Mechanism
Neutrophils, typically known as first-line immune responders, are also present in the tumor microenvironment (TME), where their role can either promote or inhibit cancer progression. A team led by Mikaël Pittet, a full professor at UNIGE and a member of Ludwig Lausanne, discovered that tumors induce a specific genetic program in neutrophils. This program leads to the continuous maturation of these cells into a terminal 'aged' state, characterized by elevated CCL3 expression (CCL3hi).
These senescent, CCL3hi neutrophils preferentially occupy oxygen-deprived regions within the TME. In these hypoxic conditions, they activate specific genetic subroutines to adapt and subsequently promote tumor cell growth and survival. The research further detailed that CCL3 produced by TANs interacts with a receptor called CCR1 on the neutrophils' surface. This interaction transmits signals that drive TANs toward the terminally aged state, bolster their survival in hypoxic microenvironments, and activate pro-tumor gene expression programs. Experiments in mice demonstrated that without CCL3 in neutrophils, or without CCR1 on their surface, the neutrophils lost their tumor-supporting capabilities while maintaining normal physiological functions.
Overcoming Research Challenges
Studying neutrophils presents technical and bioinformatics challenges due to their extremely low levels of RNA transcripts, which makes conventional single-cell RNA sequencing (scRNAseq) insufficient for parsing their cellular states. To address this, Pittet's team developed a computational probability classifier. This novel method allowed them to sort neutrophils into distinct functional states based on raw sequencing data. The method was applied to over 190 human and murine tumors, including retrospective analyses of existing datasets, consistently revealing the terminal CCL3hi state across the diverse tumor types examined. Evangelia Bolli and Pratyaksha Wirapati were identified as co-lead and co-first authors, respectively, for their contributions to the research methodologies.
Implications for Cancer Prognosis and Treatment
The conserved pro-tumor state of these CCL3hi TANs suggests their potential as a biomarker for predicting patient prognoses across multiple cancer types. The identification of CCL3 as a key molecule in this process provides a new variable for understanding tumor progression.
Furthermore, the study suggests that the genetic and biochemical circuits ensuring the survival and pro-tumor activity of CCL3hi TANs, particularly the CCL3-CCR1 signaling axis, could be targeted for cancer treatment.
This discovery complements previous research by Pittet's team in 2023, published in Science, which identified that the ratio of two genes (CXCL9 and SPP1) expressed by macrophages could predict cancer patient outcomes. The current study positions CCL3hi TANs as a second significant variable with similar prognostic implications across different tumor types and species.
Research Support
The study received support from various organizations, including the Ludwig Institute for Cancer Research, the Swiss National Science Foundation, and the U.S. National Institutes of Health.