LCL161 enhances expansion and survival of engineered anti-tumor T cells but is restricted by death signaling
BackgroundThe 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 wi...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-04-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1179827/full |
| _version_ | 1797845507066822656 |
|---|---|
| author | Arya Afsahi Arya Afsahi Arya Afsahi Christopher M. Silvestri Christopher M. Silvestri Christopher M. Silvestri Allyson E. Moore Allyson E. Moore Allyson E. Moore Carly F. Graham Carly F. Graham Carly F. Graham Kaylyn Bacchiochi Kaylyn Bacchiochi Martine St-Jean Christopher L. Baker Christopher L. Baker Christopher L. Baker Robert G. Korneluk Shawn T. Beug Shawn T. Beug Shawn T. Beug Eric C. LaCasse Jonathan L. Bramson Jonathan L. Bramson Jonathan L. Bramson |
| author_facet | Arya Afsahi Arya Afsahi Arya Afsahi Christopher M. Silvestri Christopher M. Silvestri Christopher M. Silvestri Allyson E. Moore Allyson E. Moore Allyson E. Moore Carly F. Graham Carly F. Graham Carly F. Graham Kaylyn Bacchiochi Kaylyn Bacchiochi Martine St-Jean Christopher L. Baker Christopher L. Baker Christopher L. Baker Robert G. Korneluk Shawn T. Beug Shawn T. Beug Shawn T. Beug Eric C. LaCasse Jonathan L. Bramson Jonathan L. Bramson Jonathan L. Bramson |
| author_sort | Arya Afsahi |
| collection | DOAJ |
| description | BackgroundThe 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.MethodsWe 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.ResultsLCL161 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.ConclusionsOur 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. |
| first_indexed | 2024-04-09T17:41:12Z |
| format | Article |
| id | doaj.art-eb5ca895b54b482fb6cf4a6da61045ce |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-09T17:41:12Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-eb5ca895b54b482fb6cf4a6da61045ce2023-04-17T05:59:21ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-04-011410.3389/fimmu.2023.11798271179827LCL161 enhances expansion and survival of engineered anti-tumor T cells but is restricted by death signalingArya Afsahi0Arya Afsahi1Arya Afsahi2Christopher M. Silvestri3Christopher M. Silvestri4Christopher M. Silvestri5Allyson E. Moore6Allyson E. Moore7Allyson E. Moore8Carly F. Graham9Carly F. Graham10Carly F. Graham11Kaylyn Bacchiochi12Kaylyn Bacchiochi13Martine St-Jean14Christopher L. Baker15Christopher L. Baker16Christopher L. Baker17Robert G. Korneluk18Shawn T. Beug19Shawn T. Beug20Shawn T. Beug21Eric C. LaCasse22Jonathan L. Bramson23Jonathan L. Bramson24Jonathan L. Bramson25Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, CanadaMcMaster Immunology Research Center, McMaster University, Hamilton, ON, CanadaDepartment of Medicine, McMaster University, Hamilton, ON, CanadaCentre for Discovery in Cancer Research, McMaster University, Hamilton, ON, CanadaMcMaster Immunology Research Center, McMaster University, Hamilton, ON, CanadaDepartment of Medicine, McMaster University, Hamilton, ON, CanadaCentre for Discovery in Cancer Research, McMaster University, Hamilton, ON, CanadaMcMaster Immunology Research Center, McMaster University, Hamilton, ON, CanadaDepartment of Medicine, McMaster University, Hamilton, ON, CanadaCentre for Discovery in Cancer Research, McMaster University, Hamilton, ON, CanadaMcMaster Immunology Research Center, McMaster University, Hamilton, ON, CanadaDepartment of Medicine, McMaster University, Hamilton, ON, CanadaMcMaster Immunology Research Center, McMaster University, Hamilton, ON, CanadaDepartment of Medicine, McMaster University, Hamilton, ON, CanadaApoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, CanadaCentre for Discovery in Cancer Research, McMaster University, Hamilton, ON, CanadaMcMaster Immunology Research Center, McMaster University, Hamilton, ON, CanadaDepartment of Medicine, McMaster University, Hamilton, ON, CanadaApoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, CanadaApoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, CanadaDepartment of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, CanadaCentre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, CanadaApoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, CanadaCentre for Discovery in Cancer Research, McMaster University, Hamilton, ON, CanadaMcMaster Immunology Research Center, McMaster University, Hamilton, ON, CanadaDepartment of Medicine, McMaster University, Hamilton, ON, CanadaBackgroundThe 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.MethodsWe 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.ResultsLCL161 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.ConclusionsOur 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.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1179827/fullSMAC mimeticsengineered T cellsLCL161multiple myelomacancer immunotherapyadoptive T cell therapies |
| spellingShingle | Arya Afsahi Arya Afsahi Arya Afsahi Christopher M. Silvestri Christopher M. Silvestri Christopher M. Silvestri Allyson E. Moore Allyson E. Moore Allyson E. Moore Carly F. Graham Carly F. Graham Carly F. Graham Kaylyn Bacchiochi Kaylyn Bacchiochi Martine St-Jean Christopher L. Baker Christopher L. Baker Christopher L. Baker Robert G. Korneluk Shawn T. Beug Shawn T. Beug Shawn T. Beug Eric C. LaCasse Jonathan L. Bramson Jonathan L. Bramson Jonathan L. Bramson LCL161 enhances expansion and survival of engineered anti-tumor T cells but is restricted by death signaling Frontiers in Immunology SMAC mimetics engineered T cells LCL161 multiple myeloma cancer immunotherapy adoptive T cell therapies |
| title | LCL161 enhances expansion and survival of engineered anti-tumor T cells but is restricted by death signaling |
| title_full | LCL161 enhances expansion and survival of engineered anti-tumor T cells but is restricted by death signaling |
| title_fullStr | LCL161 enhances expansion and survival of engineered anti-tumor T cells but is restricted by death signaling |
| title_full_unstemmed | LCL161 enhances expansion and survival of engineered anti-tumor T cells but is restricted by death signaling |
| title_short | LCL161 enhances expansion and survival of engineered anti-tumor T cells but is restricted by death signaling |
| title_sort | lcl161 enhances expansion and survival of engineered anti tumor t cells but is restricted by death signaling |
| topic | SMAC mimetics engineered T cells LCL161 multiple myeloma cancer immunotherapy adoptive T cell therapies |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1179827/full |
| work_keys_str_mv | AT aryaafsahi lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT aryaafsahi lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT aryaafsahi lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT christophermsilvestri lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT christophermsilvestri lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT christophermsilvestri lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT allysonemoore lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT allysonemoore lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT allysonemoore lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT carlyfgraham lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT carlyfgraham lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT carlyfgraham lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT kaylynbacchiochi lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT kaylynbacchiochi lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT martinestjean lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT christopherlbaker lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT christopherlbaker lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT christopherlbaker lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT robertgkorneluk lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT shawntbeug lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT shawntbeug lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT shawntbeug lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT ericclacasse lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT jonathanlbramson lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT jonathanlbramson lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling AT jonathanlbramson lcl161enhancesexpansionandsurvivalofengineeredantitumortcellsbutisrestrictedbydeathsignaling |