TY - JOUR
T1 - Tumor microenvironment changes leading to resistance of immune checkpoint inhibitors in metastatic melanoma and strategies to overcome resistance
AU - Pulluri, Bhargavi
AU - Kumar, Abhijeet
AU - Shaheen, Montaser
AU - Jeter, Joanne
AU - Sundararajan, Srinath
N1 - Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017/9
Y1 - 2017/9
N2 - Immunotherapy with checkpoint inhibitors targeting CTLA-4 and/or PD-1 receptors independent of the BRAF mutational status and targeted therapy with BRAF and MEK inhibitors in BRAF V600 mutated patients have taken the forefront of advanced melanoma treatment. The main advantage of immunotherapy is its ability to provide durable responses in a subset of patients. However, significant proportions of patients either do not respond or have progression after initial response to immunotherapies. Multiple changes in the tumor microenvironment, such as down regulation of immune checkpoint ligands by tumor, alteration in interferon signaling, and activation of alternate immune suppressive pathways, have been identified as possible reasons for failure of immune checkpoint therapy. Here, we review the resistance mechanisms adopted by cancer cells to checkpoint inhibitor therapy and targeted therapy. In addition, we focus on the available and emerging evidence on tumor microenvironment modulation by BRAF/MEK inhibitor therapy and its role in improving responses to checkpoint inhibitor therapy.
AB - Immunotherapy with checkpoint inhibitors targeting CTLA-4 and/or PD-1 receptors independent of the BRAF mutational status and targeted therapy with BRAF and MEK inhibitors in BRAF V600 mutated patients have taken the forefront of advanced melanoma treatment. The main advantage of immunotherapy is its ability to provide durable responses in a subset of patients. However, significant proportions of patients either do not respond or have progression after initial response to immunotherapies. Multiple changes in the tumor microenvironment, such as down regulation of immune checkpoint ligands by tumor, alteration in interferon signaling, and activation of alternate immune suppressive pathways, have been identified as possible reasons for failure of immune checkpoint therapy. Here, we review the resistance mechanisms adopted by cancer cells to checkpoint inhibitor therapy and targeted therapy. In addition, we focus on the available and emerging evidence on tumor microenvironment modulation by BRAF/MEK inhibitor therapy and its role in improving responses to checkpoint inhibitor therapy.
KW - BRAF inhibitors
KW - Combination immunotherapy
KW - Immune checkpoint inhibitors
KW - Immunotherapy
KW - MEK inhibitors
KW - Outcomes
KW - Resistance mechanisms
KW - Targeted therapy
KW - Tumor micro-environment
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U2 - 10.1016/j.phrs.2017.07.006
DO - 10.1016/j.phrs.2017.07.006
M3 - Review article
C2 - 28690075
AN - SCOPUS:85023595993
SN - 1043-6618
VL - 123
SP - 95
EP - 102
JO - Pharmacological Research
JF - Pharmacological Research
ER -