TY - JOUR
T1 - How to make immunotherapy an effective therapeutic choice for uveal melanoma
AU - Marseglia, Mariarosaria
AU - Amaro, Adriana
AU - Solari, Nicola
AU - Gangemi, Rosaria
AU - Croce, Elena
AU - Tanda, Enrica Teresa
AU - Spagnolo, Francesco
AU - Filaci, Gilberto
AU - Pfeffer, Ulrich
AU - Croce, Michela
N1 - Funding Information:
Support for this study was provided by the Italian Ministry of Health 5?1000 Funds 2013, Fondazione San Paolo 2016 (20067) and Associazione Italiana per la Ricerca sul Cancro (AIRC, IG 17103).
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/5/1
Y1 - 2021/5/1
N2 - Uveal melanoma (UM), though a rare form of melanoma, is the most common intraocular tumor in adults. Conventional therapies of primary tumors lead to an excellent local control, but 50% of patients develop metastases, in most cases with lethal outcome. Somatic driver mutations that act on the MAP‐kinase pathway have been identified, yet targeted therapies show little efficacy in the clinics. No drugs are currently available for the G protein alpha subunits GNAQ and GNA11, which are the most frequent driver mutations in UM. Drugs targeting the YAP–TAZ pathway that is also activated in UM, the tumor‐suppressor gene BRCA1 Associated Protein 1 (BAP1) and the Splicing Factor 3b Subunit 1 gene (SF3B1) whose mutations are associated with metastatic risk, have not been developed yet. Immunotherapy is highly effective in cutaneous melanoma but yields only poor results in the treatment of UM: anti‐PD‐1 and anti‐CTLA‐4 blocking antibodies did not meet the expectations except for isolated cases. Here, we discuss how the improved knowledge of the tumor microenvironment and of the cross‐talk between tumor and immune cells could help to reshape anti‐tumor immune responses to overcome the intrinsic resistance to immune checkpoint blockers of UM. We critically review the dogma of low mutational load, the induction of immune-suppressive cells, and the expression of alternative immune checkpoint molecules. We argue that immunotherapy might still be an option for the treatment of UM.
AB - Uveal melanoma (UM), though a rare form of melanoma, is the most common intraocular tumor in adults. Conventional therapies of primary tumors lead to an excellent local control, but 50% of patients develop metastases, in most cases with lethal outcome. Somatic driver mutations that act on the MAP‐kinase pathway have been identified, yet targeted therapies show little efficacy in the clinics. No drugs are currently available for the G protein alpha subunits GNAQ and GNA11, which are the most frequent driver mutations in UM. Drugs targeting the YAP–TAZ pathway that is also activated in UM, the tumor‐suppressor gene BRCA1 Associated Protein 1 (BAP1) and the Splicing Factor 3b Subunit 1 gene (SF3B1) whose mutations are associated with metastatic risk, have not been developed yet. Immunotherapy is highly effective in cutaneous melanoma but yields only poor results in the treatment of UM: anti‐PD‐1 and anti‐CTLA‐4 blocking antibodies did not meet the expectations except for isolated cases. Here, we discuss how the improved knowledge of the tumor microenvironment and of the cross‐talk between tumor and immune cells could help to reshape anti‐tumor immune responses to overcome the intrinsic resistance to immune checkpoint blockers of UM. We critically review the dogma of low mutational load, the induction of immune-suppressive cells, and the expression of alternative immune checkpoint molecules. We argue that immunotherapy might still be an option for the treatment of UM.
KW - Anti‐CTLA‐4
KW - Anti‐PD‐1
KW - BAP1
KW - Immunotherapy
KW - TIL
KW - Tumor microenvironment
KW - Uveal
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U2 - 10.3390/cancers13092043
DO - 10.3390/cancers13092043
M3 - Review article
AN - SCOPUS:85104533545
VL - 13
SP - 2043
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 9
ER -