Response of metastatic mouse invasive lobular carcinoma to mTOR inhibition is partly mediated by the adaptive immune system

Response of metastatic mouse invasive lobular carcinoma to mTOR inhibition is partly mediated by the adaptive immune system

Klarenbeek, Sjoerd (Netherlands Cancer Institute; Oncode Institute)
Doornebal, Chris W. (Oncode Institute; Netherlands Cancer Institute; Amsterdam UMC)
Kas, Sjors M. (Netherlands Cancer Institute; Oncode Institute)
Bonzanni, Nicola (Oncode Institute; Netherlands Cancer Institute; ENPICOM)
Bhin, Jinhyuk (Netherlands Cancer Institute; Oncode Institute)
Braumuller, Tanya M. (Netherlands Cancer Institute; Oncode Institute)
van der Heijden, Ingrid (Netherlands Cancer Institute; Oncode Institute)
de Bruijn, Roebi (Netherlands Cancer Institute; Oncode Institute)
Wessels, L.F.A. (TU Delft Pattern Recognition and Bioinformatics; Oncode Institute; Netherlands Cancer Institute)

2020

Effective treatment of invasive lobular carcinoma (ILC) of the breast is hampered by late detection, invasive growth, distant metastasis, and poor response to chemotherapy. Phosphoinositide 3-kinase (PI3K) signaling, one of the major druggable oncogenic signaling networks, is frequently activated in ILC. We investigated treatment response and resistance to AZD8055, an inhibitor of mammalian target of rapamycin (mTOR), in the K14-cre;Cdh1^Flox/Flox;Trp53^Flox/Flox (KEP) mouse model of metastatic ILC. Inhibition of mTOR signaling blocked the growth of primary KEP tumors as well as the progression of metastatic disease. However, primary tumors and distant metastases eventually acquired resistance after long-term AZD8055 treatment, despite continued effective suppression of mTOR signaling in cancer cells. Interestingly, therapeutic responses were associated with increased expression of genes related to antigen presentation. Consistent with this observation, increased numbers of tumor-infiltrating major histocompatibility complex class II-positive (MHCII+) immune cells were observed in treatment-responsive KEP tumors. Acquisition of treatment resistance was associated with loss of MHCII+ cells and reduced expression of genes related to the adaptive immune system. The therapeutic efficacy of mTOR inhibition was reduced in Rag1^−/- mice lacking mature T and B lymphocytes, compared to immunocompetent mice. Furthermore, therapy responsiveness could be partially rescued by transplanting AZD8055-resistant KEP tumors into treatment-naïve immunocompetent hosts. Collectively, these data indicate that the PI3K signaling pathway is an attractive therapeutic target in invasive lobular carcinoma, and that part of the therapeutic effect of mTOR inhibition is mediated by the adaptive immune system.

immune system
Invasive lobular carcinoma
mouse model
mTOR
therapy

http://resolver.tudelft.nl/uuid:3ce2975e-c1eb-4d3b-8159-a82a41e43532

https://doi.org/10.1080/2162402X.2020.1724049

2162-4011

OncoImmunology, 9 (1)

Institutional Repository

journal article

© 2020 Sjoerd Klarenbeek, Chris W. Doornebal, Sjors M. Kas, Nicola Bonzanni, Jinhyuk Bhin, Tanya M. Braumuller, Ingrid van der Heijden, Roebi de Bruijn, L.F.A. Wessels, More Authors