Combination therapy with proteasome inhibitors and TLR agonists enhances tumour cell death and IL-1β production.

Autor:	Tang AC; Department of Microbiology & Immunology, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada., Rahavi SM; Experimental Medicine Program, University of British Columbia, BC Children's Hospital, Vancouver, BC, Canada., Fung SY; Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada., Lu HY; Experimental Medicine Program, University of British Columbia, BC Children's Hospital, Vancouver, BC, Canada.; Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada., Yang H; Department of Respiratory Medicine, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China., Lim CJ; Experimental Medicine Program, University of British Columbia, BC Children's Hospital, Vancouver, BC, Canada.; Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada., Reid GS; Experimental Medicine Program, University of British Columbia, BC Children's Hospital, Vancouver, BC, Canada.; Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada., Turvey SE; Department of Microbiology & Immunology, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada. sturvey@cw.bc.ca.; Experimental Medicine Program, University of British Columbia, BC Children's Hospital, Vancouver, BC, Canada. sturvey@cw.bc.ca.; Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada. sturvey@cw.bc.ca.
Jazyk:	angličtina
Zdroj:	Cell death & disease [Cell Death Dis] 2018 Feb 07; Vol. 9 (2), pp. 162. Date of Electronic Publication: 2018 Feb 07.
DOI:	10.1038/s41419-017-0194-1
Abstrakt:	Proteasome inhibitors have emerged as an effective therapy for the treatment of haematological malignancies; however, their efficacy can be limited by the development of tumour resistance mechanisms. Novel combination strategies including the addition of TLR adjuvants to increase cell death and augment immune responses may help enhance their effectiveness. Although generally thought to inhibit inflammatory responses and NF-κB activation, we found that under specific conditions proteasome inhibitors can promote inflammatory responses by mediating IL-1β maturation and secretion after TLR stimulation. This was dependent on the timing of proteasome inhibition relative to TLR stimulation where reversal of treatment order could alternatively increase or inhibit IL-1β secretion (P < 0.001). TLR stimulation combined with proteasome inhibition enhanced cell death in vitro and delayed tumour development in vivo in NOD SCID mice (P < 0.01). However, unlike IL-1β secretion, cell death occurred similarly regardless of treatment order and was only partially caspase dependent, possessing characteristics of both apoptosis and necrosis as indicated by activation of caspase-1, 3, 8 and RIP3 phosphorylation. Although stimulation of various TLRs was capable of driving IL-1β production, TLR4 stimulation was the most effective at increasing cell death in THP-1 and U937 cells. TLR4 stimulation and proteasome inhibition independently activated the RIP3 necroptotic pathway and ultimately reduced the effectiveness of caspase/necroptosis inhibitors in mitigating overall levels of cell death. This strategy of combining TLR stimulation with proteasome inhibition may improve the ability of proteasome inhibitors to generate immunogenic cell death and increase anti-tumour activity.
Databáze:	MEDLINE
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