InVivoMAb anti-rat Kappa Immunoglobulin Light Chain

Neutrophils are a prominent component of the tumor microenvironment (TME) that can have both pro- and antitumor functions. By analyzing neutrophils across different human cancers, we revealed an ICAM1high subset enriched in the TME, which was also observed in murine triple-negative breast cancer (TNBC) models. ICAM1high neutrophils exhibited an enhanced capacity for cell-cell adhesion specifically with tumor cells retaining epithelial features, and this adhesion conferred mutual advantages to both cell types. In contrast, cancer cells with mesenchymal-like phenotypes were vulnerable to neutrophil-mediated cytotoxicity due to decreased cell adhesion and elastase resistance. These opposite effects drove tumor evolution toward a dichotomy of neutrophil-enriched, epithelial-like ecosystems and macrophage-enriched, mesenchymal-like ecosystems. As ICAM1high neutrophils can reverse migrate from tissue into the circulation, the adhesive and reverse migratory properties together mediate metastatic intravasation. Spatial transcriptomic and tissue microarray analyses demonstrated interactions between tumor cells, neutrophils, and endothelial cells in human TNBC, particularly in non-Hispanic Europeans compared with African American patients. Together, this study demonstrated tumor-immune coevolution in which neutrophils instruct the phenotypes and metastatic behaviors of TNBC, which may preferentially occur in patients of certain ancestries.

Liver metastases are frequent and challenging to treat owing to the liver's metabolically active and immune-tolerant environment. However, how cancer cells exploit nutrient availability in the liver to evade immune surveillance remains unknown. Here we show that cancer cells use the palmitate availability in the liver to impair the neutrophil antitumour function. Mechanistically, we find that breast and colorectal cancer cells metastasizing to the liver, but not the lung, require the palmitoyltransferase 17 (DHHC17, gene name ZDHHC17) to stabilize laminin-511 enabling its secretion. In turn, neutrophils in the liver metastasis environment respond to laminin-511 by decreasing their cancer cell-killing capacity. Consistently, silencing ZDHHC17 in cancer cells decreases liver metastases only in the presence of neutrophils, while metastasis growth is restored in ZDHHC17-silenced metastases upon injection of laminin-511 or inhibition of neutrophil degranulation. Taken together, we find that liver palmitate not only supports tumour intrinsic processes but also enables immune evasion.

Understanding the host immune response to SARS-CoV-2 infection is critical for developing effective immunotherapeutic interventions. Using bulk RNA sequencing of lung tissue from mock-infected and mouse-adapted SARS-CoV-2 strain MA-10-infected mice, we identified CXCL9, CXCL10, and CXCL11 as among the most upregulated transcripts. Notably, their shared receptor, CXCR3, was also upregulated, suggesting activation of the CXCL9/10/11-CXCR3 axis in the lungs. Using spectral flow cytometry, we observed that the increased recruitment of CXCR3+ immune cells, particularly T cells, innate lymphoid cells (ILCs), and macrophages, correlated with milder disease outcome. Blocking CXCR3 signaling using monoclonal antibodies resulted in worsened disease, which was accompanied by reduced recruitment of T cells, ILCs, and macrophages, and a marked increase in neutrophil infiltration. Depletion of neutrophils using αLy6G antibodies in CXCR3-blocked mice alleviated disease severity, indicating that CXCR3 signaling mitigated neutrophil-driven pathology. CXCR3 blockade failed to exacerbate disease in RAG2-/- mice, suggesting that CXCR3-mediated protection requires adaptive immune cells. Adoptive transfer of CD4+ T cells from wild type (WT), but not CXCR3-/-, mice conferred protection in RAG2-/- mice. Together, our findings establish a protective role for CXCR3-recruited T cells blocking neutrophil infiltration in the lung, highlighting the mechanistic importance of the CXCL9/10/11-CXCR3 axis in protecting the lung from SARS-CoV-2 infection.