Miguel Quintela Fandino, Director of Clinical Research Program at Spanish National Cancer Research Centre (CNIO), shared on LinkedIn:
“We have tackled how hypoxic tumors are resistant to immunotherapy – new paper out at the Journal of Clinical Investigation Osteopontin (SPP1) mediates resistance to anti-PD-1/PD-L1 agents in solid tumors. Take-home messages:
- Hypoxic tumors overexpress PD-L1; however, they a re refractory to anti-PD-1/PD-L1
- HIF also increases expression of SPP1. SPP1 is a very powerful monocyte attractor (more than VEGF) and differentiates them into M2-macrophages, which perpetuate hypoxia and induce differentiation of naive T-cells to immunosuppressor T-regs
- SPP1 also impairs tumor antigen presentation, inducing a tolerogenic phenotype.
- When SPP1 is removed (achieved both in a knockout model by genetic deletion and with a tool antibody) , 1) hypoxia is abrogated; 2) M2-type macrophages are eliminated; 3) sensitivity to anti-PD-1/L1 is restored
- The primary source of SPP1 in an hypoxic tumor is the epithelial compartment, not the myeloid compartment (demonstrated with a mouse chimeric model)
Broad implications for cancer immunotherapy just unlocked at the Spanish National Cancer Research Centre (CNIO) Breast Cancer Group!
Special thanks to the funding agencies/bodies (Instituto de Salud Carlos III , Comunidad de Madrid, Familia de Eva Plaza, Excelencia Severo Ochoa) and all the lab members. ”
Title: Osteopontin mediates acquired resistance to hypoxia-inducing antiangiogenics and promotes anti–PD-L1 refractoriness in breast cancer models
Authors: Jose Luis Ruiz-Sepulveda, Maria J. Bueno, Silvana Mouron, Veronica Jimenez-Renard, Manuel Muñoz, Manuel Moradiellos, Leonardo D. Garma, Luis García-Jimeno, Adam W.
Watson, Ghassan Mouneimne, Solip Park, Rebeca Jimeno, Miguel Quintela-Fandino
Read the full article.
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