Abstract
Oncogenic mouse double minute 2 homolog (MDM2) is an E3-ubiquitin ligase that facilitates proteasomal degradation of p53. MDM2 amplification occurs in cancer and has been implicated in accelerated tumor growth, known as hyper-progression, following immune-checkpoint therapy. MDM2 amplification also predicts poor response to immune-checkpoint inhibitors. We sought to evaluate the role of MDM2 in T-cell-mediated immune resistance. Ovarian clear cell carcinoma cell lines carrying wild-type p53 with low/high MDM2 expression were investigated in a T-cell co-culture system evaluating T-cell-mediated tumor killing. Targeting of MDM2 was achieved by siRNA transfection or a selective MDM2 inhibitor, AMG-232 and tumor cells were tested in the T-cell co-culture system. AMG-232 activated p53 signaling in cancer cells and relative resistance to AMG-232 was observed in high MDM2-expressing cell lines. Cell lines with high MDM2 expression were more resistant to T cell-mediated tumor killing. Targeting MDM2 by gene-silencing or pharmacological blockade with AMG-232 enhanced T-cell killing of cancer cells. AMG-232 potentiated tumor cell killing by T-cells in combination with anti-PD-1 antibody treatment, regardless of changes in PD-L1 expression. The AMG-232 was not toxic to the T-cells. MDM2 inhibition lowered expression of Interleukin-6, a pro-inflammatory pro-tumorigenic cytokine. Our data support targeting MDM2 in tumors with overexpression or amplification of MDM2 as a precision therapy approach to overcome drug resistance including hyper-progression in the context of immune checkpoint therapy.
Highlights
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment with significant responses for a variety of previously refractory tumors
High mouse double minute 2 homolog (MDM2) expression contributes to immune evasion by cancer cells We examined MDM2 expression in a panel of three wild-type p53-expressing human ovarian clear cell carcinoma cell lines and found higher expression of MDM2 (OVTOKO and OVMANA) as compared to TOV-21G (Fig. 1a)
MDM2 amplification in tumor cells has recently been suggested as a potential biomarker for hyper-progressive disease (HPD) that is observed in some patients (5–29%) after ICI therapy, suggesting a potential role of MDM2 overexpression in cancer cell immune evasion[3,4]
Summary
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment with significant responses for a variety of previously refractory tumors. Primary or acquired therapy resistance in about two-thirds of patients receiving ICIs remains as a major challenge[1]. In addition to primary resistance, another challenge is the phenomenon known as hyper-progressive disease (HPD), i.e. the acceleration of tumor growth after ICIs observed in 5–29% of patients. Official journal of the Cell Death Differentiation Association. Sahin et al Cell Death Discovery (2020)6:57 pharmacological inhibition with AMG-232. Our findings provide preclinical evidence for targeting MDM2 as a reasonable approach to overcome T-cell-mediated immune resistance or HPD and to design more effective cancer immunotherapy strategies
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