Open AccessTargeting Axl favors an antitumorigenic microenvironment that enhances immunotherapy responses by decreasing Hif-1α levels
Author(s) -
Marie-Anne Goyette,
Islam Elkholi,
Chloé Apcher,
Hellen Kuasne,
Carla V. Rothlin,
William J. Muller,
Darren E. Richard,
Morag Park,
JeanPhilippe Gratton,
JeanFrançois Côté
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2023868118
Subject(s) - tumor microenvironment , immunotherapy , cancer research , hypoxia (environmental) , medicine , metastasis , receptor tyrosine kinase , proinflammatory cytokine , cancer , immunology , immune system , receptor , chemistry , tumor cells , inflammation , organic chemistry , oxygen
Significance A significant pool of HER2+ breast cancer patients are either unresponsive or become resistant to standards of care. New therapeutic approaches exploiting the tumor microenvironment, including immunotherapies, are attractive. Hypoxia shapes the tumor microenvironment toward therapy resistance and metastasis. Here, we report a role for AXL receptor tyrosine kinase in the hypoxic response by promoting HIF-1α expression. Interfering with Axl in a preclinical model of HER2+ breast cancer normalizes the blood vessels and promotes a proinflammatory microenvironment that enhances immunotherapy response to reduce the primary and metastatic tumor burdens. Clinical trials so far suggest that achieving immunotherapy responses in HER2+ cancers might be challenging, and our data might provide an important insight to circumvent a roadblock.