Translation reprogramming and wobble tRNA modification in neutrophils during breast cancer development

Tumours maximize their chance to grow and to metastasize by evoking a systemic inflammation that culminates in expansion and polarization of a specific neutrophil population, known as G-MDSCs. Increasing evidences show MDSCs are important components of breast tumour development, and M- and G-MDSC are greatly enhanced in breast cancer. These cells show an immunosuppressive activity, lowering innate immunity and promoting tumour growth and metastasis development. Importantly, our laboratory recently highlighted the importance of wobble uridine tRNA modification (U34-TM) in the establishment of specific proteomes that sustain WNT-dependent intestinal tumour initiation, breast cancer metastasis and melanoma resistance (1-3). Strikingly, we found that U34-TM enzymes (i.e. Elp3, Alkbh8 and Ctu1/2) are up-regulated in neutrophils extracted from mice bearing breast tumours, as compared to neutrophils from naïve mice. Here, we hypothesized that U34-TM sustains translation reprogramming in neutrophils during breast cancer development. We generated an U34-TM loss-of-function model in neutrophils by crossing the Elp3lox/lox mouse strain with the neutrophil specific Mrp8-CRE strain. Our results show that the absence of Elp3 strongly impacted the number of neutrophils in the bone marrow, the spleen and the lung of tumour bearing mice. Surprisingly, this is correlated with a strong inhibition of tumour growth. Both the number and the size of primary breast tumours were dramatically reduced. Moreover, the metastases burden is also inhibited in PyMT mice upon Elp3 deficiency in neutrophils. Single data show that G-MDSC in the KO Elp3 mouse lose their immunosuppressive capacity which could, partially, explain the reduced tumour growth. These results indicate that U34-TM plays a key role in neutrophils during breast cancer development. Our future work will be dedicated to dissect the immune cells regulation underlying the antitumoral effect, and to identify the translation changes taking place in neutrophils during breast cancer development