ICAM1low defines a population of tumor-associated neutrophils that promote optimal response to chemotherapy and are regulated by the microbiota

Authors

• RE Araya
• KC Lam
• A Huang
• Q Chen
• A Gaines
• N Mihelson
• M Di Modica
• L Magalhaes
• RS Goldszmid

Abstract

Neutrophils are rapidly recruited to sites of acute inflammation and infection. Although their function in host defense is clear, the role of neutrophils in the tumor microenvironment remains controversial. Particularly, their role in response to cancer therapy and the signals that control their polarization towards pro- or anti-tumorigenic remain unclear. We tackled these questions with two approaches: using phenotypic, functional and transcriptional characterization of tumor-associated neutrophils (TANs) and circulating neutrophils from mouse tumor models with different susceptibility to oxaliplatin (oxa); or from oxa-sensitive tumors in microbiota-competent (SPF) or deficient animals (GF or Abx). We found that the number of reactive oxygen species (ROS)-producing TANs positively correlate with therapy efficacy, and tumors lacking TANs did not produce the ROS needed for an adequate response to oxa. However, no differences were observed in circulating neutrophils, indicating a TAN-specific requirement for successful therapy. Phenotypic characterization revealed low levels of ICAM1 expression only in TANs from oxa-susceptible tumors, identifying a possible biomarker for tumors likely to respond to this therapy. Oxa-susceptible tumors injected in GF or Abx versus SPF mice showed a significant reduction in neutrophil function, recruitment and activation pathways, significantly lower number of TANs, ROS production, and impaired response. Administration of a NOD2 ligand restored ROS production in TANs from Abx-treated mice, providing a mechanistic pathway by which microbiota can modulate neutrophil function and anti-tumor response. Our study underscores the importance of dissecting the heterogeneity of tumor-associated neutrophils and the necessary environmental factors regulating their function for successful therapeutic strategies.

Scientific Focus Area: Immunology

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