Bcl-xL targeting eliminates ageing tumor-promoting neutrophils and inhibits lung tumor growth

Elevated peripheral blood and tumor-infiltrating neutrophils are often associated with a poor patient prognosis. However, therapeutic strategies to target these cells are difficult to implement due to the life-threatening risk of neutropenia. In a genetically engineered mouse model of lung adenocarcinoma, tumor-associated neutrophils (TAN) demonstrate tumor-supportive capacities and have a prolonged lifespan compared to circulating neutrophils. Here, we show that tumor cell-derived GM-CSF triggers the expression of the anti-apoptotic Bcl-xL protein and enhances neutrophil survival through JAK/STAT signaling. Targeting Bcl-xL activity with a specific BH3 mimetic, A-1331852, blocked the induced neutrophil survival without impacting their normal lifespan. Specifically, oral administration with A-1331852 decreased TAN survival and abundance, and reduced tumor growth without causing neutropenia. We also show that G-CSF, a drug used to combat neutropenia in patients receiving chemotherapy, increased the proportion of young TANs and augmented the anti-tumor effect resulting from Bcl-xL blockade. Finally, our human tumor data indicate the same role for Bcl-xL on pro-tumoral neutrophil survival. These results altogether provide preclinical evidence for safe neutrophil targeting based on their aberrant intra-tumor longevity.|Tumor-associated neutrophils (TAN) survive extensively in the lung tumor microenvironment and increase expression of the anti-apoptotic protein Bcl-xL via GM-CSF-induced JAK/STAT signaling. Blockade of Bcl-xL decreases TAN ageing, reducing tumor growth in a mouse model of lung adenocarcinoma.Expression of the anti-apoptotic Bcl-xL is higher in TANs than in neutrophils outside tumors, and continues to increase as they age. Blockade of Bcl-xL selectively targets old, SiglecF-positive, tumor-supportive TANs, while preserving normal neutrophils and younger TANs. In vivo inhibition of Bcl-xL delays tumor growth in a mouse model of lung adenocarcinoma. Neutrophil depletion interferes with the anti-tumor efficacy of Bcl-xL blockade. The use of the anti-neutropenic agent G-CSF potentiates the anti-tumor effect of Bcl-xL inhibition.|Tumor-associated neutrophils (TAN) survive extensively in the lung tumor microenvironment and increase expression of the anti-apoptotic protein Bcl-xL via GM-CSF-induced JAK/STAT signaling. Blockade of Bcl-xL decreases TAN ageing, reducing tumor growth in a mouse model of lung adenocarcinoma.