TY - JOUR
T1 - A TLR7 agonist strengthens T and NK cell function during BRAF-targeted therapy in a preclinical melanoma model
AU - Bellmann, Lydia
AU - Cappellano, Giuseppe
AU - Schachtl-Riess, Johanna F.
AU - Prokopi, Anastasia
AU - Seretis, Athanasios
AU - Ortner, Daniela
AU - Tripp, Christoph H.
AU - Brinckerhoff, Constance E.
AU - Mullins, David W.
AU - Stoitzner, Patrizia
N1 - Publisher Copyright:
© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC
PY - 2020/3/1
Y1 - 2020/3/1
N2 - Therapeutic success of targeted therapy with BRAF inhibitors (BRAFi) for melanoma is limited by resistance development. Observations from preclinical mouse models and recent insights into the immunological effects caused by BRAFi give promise for future development of combination therapy for human melanoma. In our study, we used the transplantable D4M melanoma mouse model with the BRAFV600E mutation and concomitant PTEN loss in order to characterize alterations in tumor-infiltrating effector immune cells when tumors become resistant to BRAFi. We found that BRAFi-sensitive tumors displayed a pronounced inflammatory milieu characterized by high levels of cytokines and chemokines accompanied by an infiltration of T and NK cells. The tumor-infiltrating effector cells were activated and produced high levels of IFN-γ, TNF-α and granzyme B. When tumors became resistant and progressively grew, they reverted to a low immunogenic state similar to untreated tumors as reflected by low mRNA levels of proinflammatory cytokines and chemokines and fewer tumor-infiltrating T and NK cells. Moreover, these T and NK cells were functionally impaired in comparison to their counterparts in BRAFi-sensitive tumors. Their effector cell function could be restored by additional peritumoral treatment with the TLR7 agonist imiquimod, a clinically approved agent for nonmelanoma skin cancer. Indeed, resistance to BRAFi therapy was delayed and accompanied by high numbers of activated T and NK cells in tumors. Thus, combining BRAFi with an immune stimulating agent such as a TLR ligand could be a promising alternative approach for the treatment of melanoma.
AB - Therapeutic success of targeted therapy with BRAF inhibitors (BRAFi) for melanoma is limited by resistance development. Observations from preclinical mouse models and recent insights into the immunological effects caused by BRAFi give promise for future development of combination therapy for human melanoma. In our study, we used the transplantable D4M melanoma mouse model with the BRAFV600E mutation and concomitant PTEN loss in order to characterize alterations in tumor-infiltrating effector immune cells when tumors become resistant to BRAFi. We found that BRAFi-sensitive tumors displayed a pronounced inflammatory milieu characterized by high levels of cytokines and chemokines accompanied by an infiltration of T and NK cells. The tumor-infiltrating effector cells were activated and produced high levels of IFN-γ, TNF-α and granzyme B. When tumors became resistant and progressively grew, they reverted to a low immunogenic state similar to untreated tumors as reflected by low mRNA levels of proinflammatory cytokines and chemokines and fewer tumor-infiltrating T and NK cells. Moreover, these T and NK cells were functionally impaired in comparison to their counterparts in BRAFi-sensitive tumors. Their effector cell function could be restored by additional peritumoral treatment with the TLR7 agonist imiquimod, a clinically approved agent for nonmelanoma skin cancer. Indeed, resistance to BRAFi therapy was delayed and accompanied by high numbers of activated T and NK cells in tumors. Thus, combining BRAFi with an immune stimulating agent such as a TLR ligand could be a promising alternative approach for the treatment of melanoma.
KW - BRAF inhibitor resistance
KW - T cell and NK cell immunity
KW - melanoma
KW - targeted therapy
UR - http://www.scopus.com/inward/record.url?scp=85076120235&partnerID=8YFLogxK
U2 - 10.1002/ijc.32777
DO - 10.1002/ijc.32777
M3 - Article
SN - 0020-7136
VL - 146
SP - 1409
EP - 1420
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 5
ER -