LCL161 enhances expansion and survival of engineered anti-tumor T cells but is restricted by death signaling.

Autor:	Afsahi A; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada.; McMaster Immunology Research Center, McMaster University, Hamilton, ON, Canada.; Department of Medicine, McMaster University, Hamilton, ON, Canada., Silvestri CM; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada.; McMaster Immunology Research Center, McMaster University, Hamilton, ON, Canada.; Department of Medicine, McMaster University, Hamilton, ON, Canada., Moore AE; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada.; McMaster Immunology Research Center, McMaster University, Hamilton, ON, Canada.; Department of Medicine, McMaster University, Hamilton, ON, Canada., Graham CF; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada.; McMaster Immunology Research Center, McMaster University, Hamilton, ON, Canada.; Department of Medicine, McMaster University, Hamilton, ON, Canada., Bacchiochi K; McMaster Immunology Research Center, McMaster University, Hamilton, ON, Canada.; Department of Medicine, McMaster University, Hamilton, ON, Canada., St-Jean M; Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada., Baker CL; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada.; McMaster Immunology Research Center, McMaster University, Hamilton, ON, Canada.; Department of Medicine, McMaster University, Hamilton, ON, Canada., Korneluk RG; Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada., Beug ST; Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada., LaCasse EC; Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada., Bramson JL; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada.; McMaster Immunology Research Center, McMaster University, Hamilton, ON, Canada.; Department of Medicine, McMaster University, Hamilton, ON, Canada.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2023 Apr 17; Vol. 14, pp. 1179827. Date of Electronic Publication: 2023 Apr 17 (Print Publication: 2023).
DOI:	10.3389/fimmu.2023.1179827
Abstrakt:	Background: The genesis of SMAC mimetic drugs is founded on the observation that many cancers amplify IAP proteins to facilitate their survival, and therefore removal of these pathways would re-sensitize the cells towards apoptosis. It has become increasingly clear that SMAC mimetics also interface with the immune system in a modulatory manner. Suppression of IAP function by SMAC mimetics activates the non-canonical NF-κB pathway which can augment T cell function, opening the possibility of using SMAC mimetics to enhance immunotherapeutics. Methods: We have investigated the SMAC mimetic LCL161, which promotes degradation of cIAP-1 and cIAP-2, as an agent for delivering transient costimulation to engineered BMCA-specific human TAC T cells. In doing so we also sought to understand the cellular and molecular effects of LCL161 on T cell biology. Results: LCL161 activated the non-canonical NF-κB pathway and enhanced antigen-driven TAC T cell proliferation and survival. Transcriptional profiling from TAC T cells treated with LCL161 revealed differential expression of costimulatory and apoptosis-related proteins, namely CD30 and FAIM3. We hypothesized that regulation of these genes by LCL161 may influence the drug's effects on T cells. We reversed the differential expression through genetic engineering and observed impaired costimulation by LCL161, particularly when CD30 was deleted. While LCL161 can provide a costimulatory signal to TAC T cells following exposure to isolated antigen, we did not observe a similar pattern when TAC T cells were stimulated with myeloma cells expressing the target antigen. We questioned whether FasL expression by myeloma cells may antagonize the costimulatory effects of LCL161. Fas-KO TAC T cells displayed superior expansion following antigen stimulation in the presence of LCL161, suggesting a role for Fas-related T cell death in limiting the magnitude of the T cell response to antigen in the presence of LCL161. Conclusions: Our results demonstrate that LCL161 provides costimulation to TAC T cells exposed to antigen alone, however LCL161 did not enhance TAC T cell anti-tumor function when challenged with myeloma cells and may be limited due to sensitization of T cells towards Fas-mediated apoptosis. Competing Interests: JB is a co-founder and shareholder of Triumvira Immunologics and is a paid consultant for Triumvira Immunologics. JB is a co-inventor on patents related to the BCMA TAC described in this manuscript and licensed to Triumvira Immunologics. CB is paid through a sponsored research agreement with Triumvira Immunologics. EL is a co-founder, shareholder, and chief scientific officer of Protaxis Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Afsahi, Silvestri, Moore, Graham, Bacchiochi, St-Jean, Baker, Korneluk, Beug, LaCasse and Bramson.)
Databáze:	MEDLINE
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