TY - JOUR
T1 - Melanoma-secreted lysosomes trigger monocyte-derived dendritic cell apoptosis and limit cancer immunotherapy
AU - Santana-Magal, Nadine
AU - Farhat-Younis, Leen
AU - Gutwillig, Amit
AU - Gleiberman, Annette
AU - Rasoulouniriana, Diana
AU - Tal, Lior
AU - Netanely, Dvir
AU - Shamir, Ron
AU - Blau, Rachel
AU - Feinmesser, Meora
AU - Zlotnik, Oran
AU - Gutman, Haim
AU - Linde, Ian L.
AU - Reticker-Flynn, Nathan E.
AU - Rider, Peleg
AU - Carmi, Yaron
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/5
Y1 - 2020/5
N2 - The recent success of checkpoint blockade therapies has established immunotherapy as one of the most promising treatments for melanoma. Nonetheless, a complete curative response following immunotherapy is observed only in a fraction of patients. To identify what factors limit the efficacy of immunotherapies, we established mouse models that cease to respond to immunotherapies once their tumors exceed a certain stage. Analysis of the immune systems of the organisms revealed that the numbers of tumor-infiltrating dendritic cells (TIDC) drastically decreased with time. Further, in contrast to the current paradigm, once melanoma was established, TIDC did not migrate into sentinel lymph nodes. Instead, they underwent local cell death due to excessive phagocytosis of lysosomes. Importantly, TIDC were required to license the cytotoxic activity of tumor CD8þ T cells, and in their absence, T cells did not lyse melanoma cells. Our results offer a paradigm shift regarding the role of TIDC and a framework to increase the efficacy of immunotherapies.
AB - The recent success of checkpoint blockade therapies has established immunotherapy as one of the most promising treatments for melanoma. Nonetheless, a complete curative response following immunotherapy is observed only in a fraction of patients. To identify what factors limit the efficacy of immunotherapies, we established mouse models that cease to respond to immunotherapies once their tumors exceed a certain stage. Analysis of the immune systems of the organisms revealed that the numbers of tumor-infiltrating dendritic cells (TIDC) drastically decreased with time. Further, in contrast to the current paradigm, once melanoma was established, TIDC did not migrate into sentinel lymph nodes. Instead, they underwent local cell death due to excessive phagocytosis of lysosomes. Importantly, TIDC were required to license the cytotoxic activity of tumor CD8þ T cells, and in their absence, T cells did not lyse melanoma cells. Our results offer a paradigm shift regarding the role of TIDC and a framework to increase the efficacy of immunotherapies.
UR - http://www.scopus.com/inward/record.url?scp=85083861267&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-19-2944
DO - 10.1158/0008-5472.CAN-19-2944
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C2 - 32127354
AN - SCOPUS:85083861267
SN - 0008-5472
VL - 80
SP - 1942
EP - 1956
JO - Cancer Research
JF - Cancer Research
IS - 10
ER -
