RORγ Inverse Agonism Redirects Tumour-Conditioned Emergency Myelopoiesis and Attenuates Established Tumour Progression
- 1McGill University Health Centre
Abstract
Systemic inflammation is associated with poor outcomes in gastroesophageal adenocarcinoma (GEA), but how it contributes to disease progression remains unclear. We investigated retinoic acid receptor-related orphan receptor gamma (ROR{gamma}) as a regulator of tumour-conditioned myeloid responses. In treatment-naive GEA patients, elevated circulating neutrophil-to-lymphocyte ratio (cNLR) tracked with circulating ROR{gamma} positive neutrophils and tumoural spatial organization of ROR{gamma} positive myeloid cells, rather than neutrophil abundance. In syngeneic tumour models, pharmacologic ROR{gamma} inverse agonism altered marrow progenitor composition before tumour-growth divergence and remodeled myeloid organization across bone marrow, tumour and lung despite no endpoint change in circulating neutrophil proportions, which did not capture the earlier marrow response or subsequent tumour trajectory. ROR{gamma} perturbation enhanced longitudinal tumour control with PD-L1 blockade, whereas effects on metastatic establishment depended on tumour conditioning and treatment timing. These findings identify ROR{gamma} associated myeloid programming as a therapeutically tractable, context-dependent regulator linking systemic inflammation, hematopoiesis, tissue immune organization, and cancer progression.
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BibTeX
@misc{dhopareedoomah2026rorγ,
title = {{RORγ Inverse Agonism Redirects Tumour-Conditioned Emergency Myelopoiesis and Attenuates Established Tumour Progression}},
author = {I. Dhoparee-Doomah and K. Ma and A. Brassard and S. Leo and S. Hajhashemi and Y. Li and K. Milne and M. Z. Xu and M. Al Dow and A. Fouda and F. Bourdeau and B. Gordon and B. Giannias and B. Nelson and J. Spicer and L. Ferri and J. Tchervenkov and J. Cools-Lartigue},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.01.755741},
url = {https://www.biorxiv.org/content/10.64898/2026.10.01.755741v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - RORγ Inverse Agonism Redirects Tumour-Conditioned Emergency Myelopoiesis and Attenuates Established Tumour Progression
AU - I. Dhoparee-Doomah
AU - K. Ma
AU - A. Brassard
AU - S. Leo
AU - S. Hajhashemi
AU - Y. Li
AU - K. Milne
AU - M. Z. Xu
AU - M. Al Dow
AU - A. Fouda
AU - F. Bourdeau
AU - B. Gordon
AU - B. Giannias
AU - B. Nelson
AU - J. Spicer
AU - L. Ferri
AU - J. Tchervenkov
AU - J. Cools-Lartigue
PY - 2026
DA - 2026/10/01
PB - bioRxiv
DO - 10.64898/2026.10.01.755741
UR - https://www.biorxiv.org/content/10.64898/2026.10.01.755741v1
AB - Systemic inflammation is associated with poor outcomes in gastroesophageal adenocarcinoma (GEA), but how it contributes to disease progression remains unclear. We investigated retinoic acid receptor-related orphan receptor gamma (ROR{gamma}) as a regulator of tumour-conditioned myeloid responses. In treatment-naive GEA patients, elevated circulating neutrophil-to-lymphocyte ratio (cNLR) tracked with circulating ROR{gamma} positive neutrophils and tumoural spatial organization of ROR{gamma} positive myeloid cells, rather than neutrophil abundance. In syngeneic tumour models, pharmacologic ROR{gamma} inverse agonism altered marrow progenitor composition before tumour-growth divergence and remodeled myeloid organization across bone marrow, tumour and lung despite no endpoint change in circulating neutrophil proportions, which did not capture the earlier marrow response or subsequent tumour trajectory. ROR{gamma} perturbation enhanced longitudinal tumour control with PD-L1 blockade, whereas effects on metastatic establishment depended on tumour conditioning and treatment timing. These findings identify ROR{gamma} associated myeloid programming as a therapeutically tractable, context-dependent regulator linking systemic inflammation, hematopoiesis, tissue immune organization, and cancer progression.
ER -