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Characterising and targeting tumour-associated neutrophils in a model of lung squamous cell carcinoma

par Defruit, Amaury
Président du jury Van Melderen, Laurence
Promoteur Meylan, Etienne
Publication Non publié, 2024-08-30

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Résumé :

Tumour-associated neutrophils (TANs) play a significant role in tumour progression, exhibiting both pro-tumour and anti-tumour activities. A subset of TANs expressing Siglec-F has been previously linked to a pro-tumoural phenotype in a KrasFrt-STOP-Frt-G12D/WT; p53Frt/Frt (KP) model of LUAD. The host laboratory further demonstrated that these long-lived Siglec-F expressing pro-tumoural TANs could be targeted using a Bcl-xL inhibitor in the LUAD model. To interrogate whether such findings could be generalised to another subtype of non-small cell lung cancer (NSCLC), namely the lung squamous cell carcinoma (LUSC), we conducted a broad immune study of tumours in our SNL GEMM. This profiling revealed substantial TAN infiltration. We further characterised the presence of the long-lived Siglec-F+ TANs. While we could confirm the effect of Bcl-xL blockade to induce the apoptosis of these Siglec-F+ TANs, and the recruitment of new Siglec-F- TANs, the therapy did not affect tumour growth. Instead, flow cytometry revealed whole TAN pool depletion, that was mitigated when reducing A- 1331852 dosage frequency. In vitro, studies on peripheral blood neutrophils cultured in cancer cell-line supernatant showed that A-1331852 could at least reduce the increased lifespan induced by the cell-line secreted factors. Collectively, our results highlight the potential differences of Bcl-xL blockade in the two subtypes of NSCLC. Moreover, it could be interesting to combine Bcl-xL blockade with αPD-L1 ICI or CXCR2 antagonist, to interrogate whether in combination we could observe an effect on tumour growth.