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 CD8+ 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. SIGNIFICANCE: This work redefines the role of monocyte-derived dendritic cells in melanoma and provides a novel strategy to increase the efficacy of T-cell-based immunotherapies in nonresponding individuals. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/10/1942/F1.large.jpg.
Highlights
Patients with advanced melanoma have very poor prognosis and must undergo a series of excruciating treatments of chemotherapy, oncogene inhibitors, or combined therapy [1]
The general convention suggests that the capacity of tumor cells to edit their presented antigen and their ability to promote a suppressive microenvironment is what restricts the number of melanoma-infiltrating cytotoxic T cells with a limited T-cell receptor (TCR) repertoire [11,12,13,14]
We found that in contrast to the current paradigm, melanomainfiltrating MoDC do not migrate into sentinel lymph nodes, but rather are required in situ to license the cytotoxic activity of CD8þ T cells
Summary
Patients with advanced melanoma have very poor prognosis and must undergo a series of excruciating treatments of chemotherapy, oncogene inhibitors, or combined therapy [1]. A number of seminal papers have established a direct correlation between a high frequency of cytotoxic T cells in the tumor mass and improved clinical out-. Pioneering therapies based on de novo expansion of tumor-infiltrating cytotoxic T cells and their reinfusion to the patient demonstrated the capability of the immune system to mediate tumor rejection [4, 5]. Clinical responses were observed in patients with melanoma treated with blocking antibodies directed against suppressive receptors on T cells [6, 7]. The general convention suggests that the capacity of tumor cells to edit their presented antigen and their ability to promote a suppressive microenvironment is what restricts the number of melanoma-infiltrating cytotoxic T cells with a limited T-cell receptor (TCR) repertoire [11,12,13,14]
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