Immunosuppressive reprogramming of neutrophils by lung mesenchymal cells promotes breast cancer metastasis

Abstract

Neutrophils, the most abundant innate immune cells, function as crucial regulators of the adaptive immune system in diverse pathological conditions, including metastatic cancer. However, it remains largely unknown whether their immunomodulatory functions are intrinsic or acquired within the pathological tissue environment. Here, using mouse models of metastatic breast cancer in the lungs, we show that, although neutrophils isolated from bone marrow (BM) or blood are minimally immunosuppressive, lung-infiltrating neutrophils are robustly suppressive of both T cells and natural killer (NK) cells. We found that this tissue-specific immunosuppressive capacity of neutrophils exists in the steady state and is reinforced by tumor-associated inflammation. Acquisition of potent immunosuppression activity by lung-infiltrating neutrophils was endowed by the lung-resident stroma, specifically CD140a + mesenchymal cells (MCs) and largely via prostaglandin-endoperoxide synthase 2 (PTGS2), the rate-limiting enzyme for prostaglandin E 2 (PGE 2 ) biosynthesis. MC-specific deletion of Ptgs2 or pharmacological inhibition of PGE 2 receptors reversed lung neutrophil–mediated immunosuppression and mitigated lung metastasis of breast cancer in vivo. These lung stroma–targeting strategies substantially improved the therapeutic efficacy of adoptive T cell–based immunotherapy in treating metastatic disease in mice. Collectively, our results reveal that the immunoregulatory effects of neutrophils are induced by tissue-resident stroma and that targeting tissue-specific stromal factors represents an effective approach to boost tissue-resident immunity against metastatic disease.

Nanotechnology Reprogramming Metabolism for Enhanced Tumor Immunotherapy

“…The involvement of these cells should be considered in future research, as their metabolic contributions may result in tissue-specific immunosuppression. 10 Importantly, many therapeutic nanomedicines reach their intracellular targets via endocytosis. 182 Therefore, other than tumor cells, tumor targeting nanoparticles could be most easily internalized by antigen-presenting cells with phagocytic functions, such as DCs and macrophages.…”

“…Lipid metabolism of both tumor cells and neutrophils in the TME can profoundly influence TAN recruitment and function, and tumor-derived oxysterols contribute to neutrophil recruitment . Recent research demonstrated that in the lung microenvironment, lung mesenchymal cells could significantly enhance the expression of immunosuppressive genes via PGE2, which explained the tissue-dependent immunosuppression of neutrophils . Importantly, in patients, ER stress-related genes can be induced in immunosuppressive neutrophils, altering lipid metabolism, and increasing the expression of ROS, arginase 1 (ARG1), and PGE2, leading to immunosuppression. ,, Thus, tumor cell lipid metabolism can promote neutrophil immunosuppressive function, and neutrophils can, in turn, contribute to the accumulation of toxic metabolites as well as nutrient depletion.…”

“…Moreover, NK activation receptors can be repressed by hypoxia and PGE2. , Therefore, targeting tumor metabolism or increasing the metabolic flexibility of NK cells may be effective strategies for enhancing NK cell antitumor immunity. Of note, PGE2 is elevated in many cancers, which suppresses the antitumor functions of other immune cells include NK cells, T cells and DCs. ,,, Hence, PGE2 metabolism may be a preferable target in tumor immunotherapies due to its broad suppression to antitumor immune cells.…”

“…In recent years, a growing number of studies have focused on the mechanisms underlying tumor-derived immunosuppression with the aim of developing improved tumor immunotherapies. Notably, several noncontact immunosuppression mechanisms have been ascribed to toxic metabolites or nutrient depletion, − connecting tumor cell metabolic profiles with immunosuppression. Cancer is a heterogeneous metabolic disease with complex metabolic profiles; accumulated mutation burdens in tumor cells result in altered metabolic profiles, leading to nutrient depletion and accumulation of toxic metabolites that can impair the antitumor functions of multiple immune cell types, hindering both adaptive and innate antitumor immunity. , Further, the diversity of genetic profiles across tumors leads to distinct metabolic features and consequent differences in immunosuppression mechanisms.…”

Charting granulopoietic disturbances in sepsis

“…They found that the eicosanoid prostaglandin E 2 (PGE 2 ) partially mediated the suppression of CD4 + T cells by neutrophils from individuals with sepsis, as an antagonist of the cognate receptor restored the expression of the lymphocyte-activation markers CD69 and PD-1, but not the proliferation of CD4 + T cells 2 . This finding is exciting and deserves further testing, also considering the multifaceted immunological functions of PGE 2 in tumor-associated neutrophils 8,9 . However, many other suppressive mechanisms are at play, such as the release of immune-modulating cytokines, reactive oxygen species (ROS), granules or neutrophil extracellular traps (NETs) 7 .…”