Glycolytic neutrophils accrued in the spleen compromise anti-tumour T cell immunity in breast cancer

Nat Metab. 2023 Aug;5(8):1408-1422. doi: 10.1038/s42255-023-00853-4. Epub 2023 Aug 10.

Abstract

The coordination of immunity across organs is fundamental to cancer development and progression. It is well known that the hostile metabolic microenvironment in the tumour is a major obstacle to effective anti-tumour immunity. However, whether metabolic alterations in secondary lymphoid tissues beyond the tumour can affect anti-tumour immunity remains elusive. Using positron-emission tomography-computed tomography, we show that the spleens of humans and mice with breast cancer are metabolically reprogrammed to a glycolytic state. Such an increase in glucose consumption in the spleen primarily occurs in neutrophils generated by extramedullary haematopoiesis and recruitment from the bone marrow. These neutrophils in the white pulp create a glucose-deprived microenvironment, which, in turn, induces T cell anergy by impairing pyruvate kinase M2 and its action on STAT5, thus compromising their anti-tumour activities. Furthermore, CCL9 chemokine produced by splenic stromal cells is central to splenic neutrophil accumulation, and blockade of the CCR1 receptor favours tumour eradication. Thus, neutrophils metabolically influence the spleen microenvironment and control anti-tumour T cell responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms* / metabolism
  • Female
  • Humans
  • Mice
  • Neutrophils / metabolism
  • Spleen* / metabolism
  • Spleen* / pathology
  • T-Lymphocytes
  • Tumor Microenvironment