TY - JOUR
T1 - Molecular pathways
T2 - Oncologic pathways and their role in T-cell exclusion and immune evasion - A new role for the AXL receptor tyrosine kinase
AU - Aguilera, Todd A.
AU - Giaccia, Amato J.
N1 - Funding Information:
The authors are supported by ASTRO Resident Seed Grant# RA2014-3 (T.A. Aguilera), the Silicon Valley Foundation, the Sydney Frank Foundation, the Kimmelman Fund (A.J. Giaccia), and the National Cancer Institute of the National Institutes of Health under award numbers T32CA121940 (T.A. Aguilera) and P01CA67166 and R35CA197713 (A.J. Giaccia).
Publisher Copyright:
©2017 AACR.
PY - 2017/6/15
Y1 - 2017/6/15
N2 - With the clinical impact of CTLA-4 and PD-1/PD-L1 immune checkpoint therapies, widespread interest in cancer immunotherapy has been ignited. However, the rate and extent of clinical responses to approved therapies are limited and often nonexistent in many solid tumors. This is partially because immune checkpoint therapies are most effective against T-cell-inflamed tumors, and non-T-cell-inflamed or T-cell-excluded tumors remain a significant barrier. New strategies are needed to overcome immune resistance mechanisms that arise during tumor development, which result in T-cell exclusion. Approaches may need to be combined with conventional therapies such as chemotherapy, radiotherapy, and molecularly targeted therapy, and many clinical trials are ongoing. This review discusses the challenge of T-cell exclusion and innate oncologic pathways that contribute to this problem, including β-catenin, STAT3, NF-κB, PTEN, and AXL tyrosine kinase. The GAS6/AXL pathway is of interest immunologically, as its targeting can lead to greater antitumor immune responses after radiotherapy. In addition, several targeted therapies that are selective and nonselective for AXL are in preclinical and clinical development in acute myelogenous leukemia and renal cell cancer. There remains much to learn, but the future is bright for anti-AXL therapies, though effective combinations and their impact may not be realized for years to come.
AB - With the clinical impact of CTLA-4 and PD-1/PD-L1 immune checkpoint therapies, widespread interest in cancer immunotherapy has been ignited. However, the rate and extent of clinical responses to approved therapies are limited and often nonexistent in many solid tumors. This is partially because immune checkpoint therapies are most effective against T-cell-inflamed tumors, and non-T-cell-inflamed or T-cell-excluded tumors remain a significant barrier. New strategies are needed to overcome immune resistance mechanisms that arise during tumor development, which result in T-cell exclusion. Approaches may need to be combined with conventional therapies such as chemotherapy, radiotherapy, and molecularly targeted therapy, and many clinical trials are ongoing. This review discusses the challenge of T-cell exclusion and innate oncologic pathways that contribute to this problem, including β-catenin, STAT3, NF-κB, PTEN, and AXL tyrosine kinase. The GAS6/AXL pathway is of interest immunologically, as its targeting can lead to greater antitumor immune responses after radiotherapy. In addition, several targeted therapies that are selective and nonselective for AXL are in preclinical and clinical development in acute myelogenous leukemia and renal cell cancer. There remains much to learn, but the future is bright for anti-AXL therapies, though effective combinations and their impact may not be realized for years to come.
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U2 - 10.1158/1078-0432.CCR-17-0189
DO - 10.1158/1078-0432.CCR-17-0189
M3 - Article
C2 - 28289089
AN - SCOPUS:85020815378
SN - 1078-0432
VL - 23
SP - 2928
EP - 2933
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 12
ER -