Targeting WEE1/AKT Restores p53-Dependent Natural Killer–Cell Activation to Induce Immune Checkpoint Blockade Responses in “Cold” Melanoma
- 19 April 2022
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Immunology Research
- Vol. 10 (6), 757-769
- https://doi.org/10.1158/2326-6066.cir-21-0587
Abstract
Immunotherapy has revolutionized cancer treatment. Unfortunately, most tumor types do not respond to immunotherapy due to a lack of immune infiltration or 'cold' tumor microenvironment (TME), a contributing factor in treatment failure. Activation of the p53 pathway can increase apoptosis of cancer cells, leading to enhanced antigen presentation, and can stimulate natural killer (NK) cells through expression of stress ligands. Therefore, modulation of the p53 pathway in cancer cells with wildtype TP53 has the potential to enhance tumor immunogenicity to NK cells, produce an inflammatory TME, and ultimately lead to tumor regression. In this study, we report simultaneous targeting of the AKT/WEE1 pathways is a novel and tolerable approach to synergistically induce p53 activation to inhibit tumor development. This approach reduced the growth of melanoma cells and induced plasma membrane surface localization of the ER-resident protein calreticulin, an indicator of immunogenic cell death (ICD). Increase in ICD led to enhanced expression of stress ligands recognized by the activating NK cell receptor NKG2D, promoting tumor lysis. WEE1/AKT inhibition resulted in recruitment and activation of immune cells, including NK cells, in the TME, triggering an inflammatory cascade that transformed the 'cold' TME of B16F10 melanoma into a 'hot' TME that responded to anti-PD-1, resulting in complete regression of established tumors. These results suggest that AKT/WEE1 pathway inhibition is a potential approach to broaden the utility of class-leading anti-PD-1 therapies by enhancing p53-mediated, NK cell-dependent tumor inflammation and supports the translation of this novel approach to further improve response rates for metastatic melanoma.Keywords
Other Versions
Funding Information
- NCI (R01CA241148)
- National Health and Medical Research Council (GNT1124784, GNT1066770, GNT1057852, GNT1124907, GNT1057812, GNT1049407, GNT1027472, GNT1184615)
- NHMRC (GNT1195296)
This publication has 70 references indexed in Scilit:
- Identification of Aurora Kinase B and Wee1-Like Protein Kinase as Downstream Targets of V600EB-RAF in MelanomaThe American Journal of Pathology, 2013
- BRAF in Melanoma: Pathogenesis, Diagnosis, Inhibition, and ResistanceJournal of Skin Cancer, 2011
- Akt inhibitors in clinical development for the treatment of cancerExpert Opinion on Investigational Drugs, 2010
- In Silico Analysis of Kinase Expression Identifies WEE1 as a Gatekeeper against Mitotic Catastrophe in GlioblastomaCancer Cell, 2010
- edgeR: a Bioconductor package for differential expression analysis of digital gene expression dataBioinformatics, 2009
- The killer's kiss: the many functions of NK cell immunological synapsesCurrent Opinion in Cell Biology, 2008
- Akt3 and Mutant V600EB-Raf Cooperate to Promote Early Melanoma DevelopmentCancer Research, 2008
- NKG2D-Deficient Mice Are Defective in Tumor Surveillance in Models of Spontaneous MalignancyImmunity, 2008
- Induced recruitment of NK cells to lymph nodes provides IFN-γ for TH1 primingNature Immunology, 2004
- Loss of HLA class I antigens by melanoma cells: molecular mechanisms, functional significance and clinial relevanceImmunology Today, 1995