Melanoma-secreted lysosomes trigger monocyte-derived dendritic cell apoptosis and limit cancer immunotherapy

Nadine Santana-Magal, Leen Farhat-Younis, Amit Gutwillig, Annette Gleiberman, Diana Rasoulouniriana, Lior Tal, Dvir Netanely, Ron Shamir, Rachel Blau, Meora Feinmesser, Oran Zlotnik, Haim Gutman, Ian L. Linde, Nathan E. Reticker-Flynn, Peleg Rider, Yaron Carmi

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1942-1956
Number of pages15
JournalCancer Research
Volume80
Issue number10
DOIs
StatePublished - May 2020

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