ATRX alteration contributes to tumor growth and immune escape in pleomorphic sarcomas

Darmusey, L.; Perot, G.; Thebault, N.; Le Guellec, S.; Desplat, N.; Gaston, L.; Delespaul, L.; Lesluyes, T.; Darbo, E.; Gomez-Brouchet, A.; Richard, E.; Baud, J.; Leroy, L.; Coindre, J. M.; Blay, J.-Y.; Chibon, F.

doi:10.1101/2020.10.23.352112

bioRxiv · 10.1101/2020.10.23.352112

ATRX alteration contributes to tumor growth and immune escape in pleomorphic sarcomas

Darmusey, L.·Perot, G.·Thebault, N.·Le Guellec, S.·Desplat, N.·Gaston, L.·Delespaul, L.·Lesluyes, T.·Darbo, E.·Gomez-Brouchet, A.·Richard, E.·Baud, J.·Leroy, L.·Coindre, J. M.·Blay, J.-Y.·Chibon, F.

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Abstract

Whole genome and transcriptome sequencing of a cohort of 67 leiomyosarcomas revealed ATRX to be one of the most frequently mutated genes in leiomyosarcomas after TP53 and RB1. While its function is well described in the alternative lengthening of telomeres mechanism, we wondered whether its alteration could have complementary effects on sarcoma oncogenesis. ATRX alteration is associated with the down-expression of genes linked to differentiation in leiomyosarcomas, and to immunity in an additional cohort of 60 poorly differentiated sarcomas. In vitro and in vivo models showed that ATRX loss increases tumor growth rate and immune escape by decreasing the immunity load of active mast cells in sarcoma tumors. These data indicate that an alternative to unsuccessful targeting of the adaptive immune system in sarcoma could be to target the innate system. This might lead to a better outcome for sarcoma patients in terms of ATRX status.

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Darmusey, L., Perot, G., Thebault, N., Le Guellec, S., Desplat, N., Gaston, L., Delespaul, L., Lesluyes, T., Darbo, E., Gomez-Brouchet, A., Richard, E., Baud, J., Leroy, L., Coindre, J. M., Blay, J.-Y., Chibon, F.. 2020-10-23. ATRX alteration contributes to tumor growth and immune escape in pleomorphic sarcomas. https://doi.org/10.1101/2020.10.23.352112

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