Dendritic Cell Vaccination in Metastatic Melanoma Turns 'Non-T Cell Inflamed' Into 'T-Cell Inflamed' Tumors

Autor: Massimo Framarini, Giorgia Gentili, Elena Pancisi, Jenny Bulgarelli, Filippo Piccinini, Massimiliano Petrini, Serena Maiocchi, Giovanni Foschi, Laura Ridolfi, Massimo Guidoboni, Valentina Ancarani, Antonella Carbonaro, Biagio Eugenio Leone, Barbara Vergani, Marcella Tazzari, Anna Maria Granato, Francesco De Rosa
Přispěvatelé: Jenny Bulgarelli, Marcella Tazzari, Anna M. Granato, Laura Ridolfi, Serena Maiocchi, Francesco de Rosa, Massimiliano Petrini, Elena Pancisi, Giorgia Gentili, Barbara Vergani, Filippo Piccinini, Antonella Carbonaro, Biagio E. Leone, Giovanni Foschi, Valentina Ancarani, Massimo Framarini and Massimo Guidoboni, Bulgarelli, J, Tazzari, M, Granato, A, Ridolfi, L, Maiocchi, S, de Rosa, F, Petrini, M, Pancisi, E, Gentili, G, Vergani, B, Piccinini, F, Carbonaro, A, Leone, B, Foschi, G, Ancarani, V, Framarini, M, Guidoboni, M
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
medicine.medical_treatment
T-Lymphocytes
CD8-Positive T-Lymphocytes
T-Lymphocytes
Regulatory
0302 clinical medicine
Cancer immunotherapy
Immunology and Allergy
Cytotoxic T cell
Melanoma Tumor Microenvironment
Dendritic Cell Vaccine T Cell Landscape Immunotherapy
immunomonitoring PDL1
dendritic cell vaccine
Lymphocytes
Neoplasm Metastasis
Original Research
Vaccination
FOXP3
Middle Aged
Regulatory
medicine.anatomical_structure
Female
immunotherapy
immunomonitoring
melanoma
PDL1
T cell landscape
tumor microenvironment
Adult
Aged
Follow-Up Studies
Humans
Inflammation
Cancer Vaccines
Dendritic Cells
Lymphocytes
Tumor-Infiltrating
Melanoma
lcsh:Immunologic diseases. Allergy
T cell
Immunology
GZMB
03 medical and health sciences
medicine
Tumor-Infiltrating
business.industry
Immunotherapy
Dendritic cell
030104 developmental biology
Cancer research
business
lcsh:RC581-607
CD8
030215 immunology
Zdroj: Frontiers in Immunology, Vol 10 (2019)
Frontiers in Immunology
ISSN: 1664-3224
DOI: 10.3389/fimmu.2019.02353/full
Popis: Dendritic cell (DC)-based vaccination effectively induces anti-tumor immunity, although in the majority of cases this does not translate into a durable clinical response. However, DC vaccination is characterized by a robust safety profile, making this treatment a potential candidate for effective combination cancer immunotherapy. To explore this possibility, understanding changes occurring in the tumor microenvironment (TME) upon DC vaccination is required. In this line, quantitative and qualitative changes in tumor-infiltrating T lymphocytes (TILs) induced by vaccination with autologous tumor lysate/homogenate loaded DCs were investigated in a series of 16 patients with metastatic melanoma. Immunohistochemistry for CD4, CD8, Foxp3, Granzyme B (GZMB), PDL1, and HLA class I was performed in tumor biopsies collected before and after DC vaccination. The density of each marker was quantified by automated digital pathology analysis on whole slide images. Co-expression of markers defining functional phenotypes, i.e., Foxp3+ regulatory CD4+ T cells (Treg) and GZMB+ cytotoxic CD8+ T cells, was assessed with sequential immunohistochemistry. A significant increase of CD8+ TILs was found in post-vaccine biopsies of patients who were not previously treated with immune-modulating cytokines or Ipilimumab. Interestingly, along with a maintained tumoral HLA class I expression, after DC vaccination we observed a significant increase of PDL1+ tumor cells, which significantly correlated with intratumoral CD8+ T cell density. This observation might explain the lack of a significant concurrent cytotoxic reactivation of CD8+ T cell, as measured by the numbers of GZMB+ T cells. Altogether these findings indicate that DC vaccination exerts an important role in sustaining or de novo inducing a T cell inflamed TME. However, the strength of the intratumoral T cell activation detected in post-DC therapy lesions is lessened by an occurring phenomenon of adaptive immune resistance, yet the concomitant PDL1 up-regulation. Overall, this study sheds light on DC immunotherapy-induced TME changes, lending the rationale for the design of smarter immune-combination therapies.
Databáze: OpenAIRE
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