Tumor-associated neutrophils: orchestrating cancer pathobiology and therapeutic resistance

ABSTRACT

Introduction: Neutrophils or polymorphonuclear cells (PMNs) account for a considerable portion of the tumor immune stroma. Emerging single-cell transcriptomic analyses have elucidated the striking cellular heterogeneity of PMNs during homeostasis and pathologic conditions and have established their diverse roles in cancer. PMNs have emerged as important players in cancer pathobiology and therapeutic resistance. Tumor-associated neutrophils (TANs) effector functions influence tumor development and resistance or response to therapy.

Areas covered: This review focuses on PMN heterogeneity and functional diversity in the context of carcinogenesis. TANs, by activating diverse signaling pathways, contribute to cancer progression and resistance to therapies. Mechanisms by which TANs impact therapeutic resistance include alterations of the tumoral DNA damage response, angiogenesis, reactivation of cancer dormancy, enhancement of tumor cell proliferation/survival and immune evasion.

Expert opinion: With the emerging phenotypic and function heterogeneity of TANs, targeting specific TAN functions in developing tumors can lead to translatable therapeutic approaches and limit drug resistance. We propose that combining specific targeting of TAN activity with standard cancer therapy can help patients achieving a complete response and prevent cancer relapse.

KEYWORDS:

• Neutrophils
• Tumor-Associated Neutrophils
• Heterogeneity
• Migration
• Cancer
• Immunotherapy
• Drug Resistance

Article Highlights

• Single-cell sequencing studies revealed tumor-associated neutrophils (TANs) to be heterogenous and plastic cells with distinct transcriptional profiles and effector functions.

• TAN heterogeneity in cancer stems from its maturation status during granulopoiesis as well as from spatial localization in the tumor.

• TANs can contribute to intrinsically or extrinsically acquired cancer resistance to therapeutics, which includes immunosuppression, DNA damage response alterations, angiogenesis, dormancy escape, and enhanced cellular proliferation/survival.

• TANs via distinct signaling pathways can interfere with major classes of cancer therapeutics, including immune checkpoint blockades, tyrosine kinase inhibitors, and cytotoxic DNA-damaging agents. TAN-directed therapy and its combination with standard care approaches could improve therapeutic sensitivity and/or deepen the clinical response in refractory cancer patients.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This work was supported by grants from the Digestive Health Foundation, American Cancer Society Research Scholar Award and Crohn’s & Colitis Foundation Senior Research Award to R Sumagin, and the Department of Defense’s Congressionally Directed Medical Research Program Horizon Award to TM Bui.