NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic non-small cell lung cancer (NSCLC) in a humanized mouse model
Expression of NPRL2/TUSC4, a tumor-suppressor gene, is reduced in many cancers including NSCLC. Restoration of NPRL2 induces DNA damage, apoptosis, and cell-cycle arrest. We investigated NPRL2 antitumor immune responses in aPD1R/KRAS/STK11mt NSCLC in humanized-mice. Humanized-mice were generated by...
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eLife Sciences Publications Ltd
2025-02-01
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| Online Access: | https://elifesciences.org/articles/98258 |
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| author | Ismail M Meraz Mourad Majidi Renduo Song Feng Meng Lihui Gao Qi Wang Jing Wang Elizabeth J Shpall Jack A Roth |
| author_facet | Ismail M Meraz Mourad Majidi Renduo Song Feng Meng Lihui Gao Qi Wang Jing Wang Elizabeth J Shpall Jack A Roth |
| author_sort | Ismail M Meraz |
| collection | DOAJ |
| description | Expression of NPRL2/TUSC4, a tumor-suppressor gene, is reduced in many cancers including NSCLC. Restoration of NPRL2 induces DNA damage, apoptosis, and cell-cycle arrest. We investigated NPRL2 antitumor immune responses in aPD1R/KRAS/STK11mt NSCLC in humanized-mice. Humanized-mice were generated by transplanting fresh human cord blood-derived CD34 stem cells into sub-lethally irradiated NSG mice. Lung-metastases were developed from KRAS/STK11mt/aPD1R A549 cells and treated with NPRL2 w/wo pembrolizumab. NPRL2-treatment reduced lung metastases significantly, whereas pembrolizumab was ineffective. Antitumor effect was greater in humanized than non-humanized-mice. NPRL2 + pembrolizumab was not synergistic in KRAS/STK11mt/aPD1R tumors but was synergistic in KRASwt/aPD1S H1299. NPRL2 also showed a significant antitumor effect on KRASmt/aPD1R LLC2 syngeneic-tumors. The antitumor effect was correlated with increased infiltration of human cytotoxic-T, HLA-DR+DC, CD11c+DC, and downregulation of myeloid and regulatory-T cells in TME. Antitumor effect was abolished upon in-vivo depletion of CD8-T, macrophages, and CD4-T cells whereas remained unaffected upon NK-cell depletion. A distinctive protein-expression profile was found after NPRL2 treatment. IFNγ, CD8b, and TBX21 associated with T-cell functions were significantly increased, whereas FOXP3, TGFB1/B2, and IL-10RA were strongly inhibited by NPRL2. A list of T-cell co-inhibitory molecules was also downregulated. Restoration of NPRL2 exhibited significantly slower tumor growth in humanized-mice, which was associated with increased presence of human cytotoxic-T, and DC and decreased percentage of Treg, MDSC, and TAM in TME. NPRL2-stable cells showed a substantial increase in colony-formation inhibition and heightened sensitivity to carboplatin. Stable-expression of NPRL2 resulted in the downregulation of MAPK and AKT-mTOR signaling. Taken-together, NPRL2 gene-therapy induces antitumor activity on KRAS/STK11mt/aPD1R tumors through DC-mediated antigen-presentation and cytotoxic immune-cell activation. |
| format | Article |
| id | doaj-art-6defc4e2b679452c98a4ec91a4251648 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj-art-6defc4e2b679452c98a4ec91a42516482025-02-11T15:57:54ZengeLife Sciences Publications LtdeLife2050-084X2025-02-011310.7554/eLife.98258NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic non-small cell lung cancer (NSCLC) in a humanized mouse modelIsmail M Meraz0https://orcid.org/0000-0001-9109-5196Mourad Majidi1Renduo Song2Feng Meng3Lihui Gao4Qi Wang5Jing Wang6Elizabeth J Shpall7Jack A Roth8Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Houston, United StatesDepartment of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Houston, United StatesDepartment of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Houston, United StatesDepartment of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Houston, United StatesDepartment of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Houston, United StatesDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Houston, United StatesDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Houston, United StatesDepartment of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, Houston, United StatesDepartment of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Houston, United StatesExpression of NPRL2/TUSC4, a tumor-suppressor gene, is reduced in many cancers including NSCLC. Restoration of NPRL2 induces DNA damage, apoptosis, and cell-cycle arrest. We investigated NPRL2 antitumor immune responses in aPD1R/KRAS/STK11mt NSCLC in humanized-mice. Humanized-mice were generated by transplanting fresh human cord blood-derived CD34 stem cells into sub-lethally irradiated NSG mice. Lung-metastases were developed from KRAS/STK11mt/aPD1R A549 cells and treated with NPRL2 w/wo pembrolizumab. NPRL2-treatment reduced lung metastases significantly, whereas pembrolizumab was ineffective. Antitumor effect was greater in humanized than non-humanized-mice. NPRL2 + pembrolizumab was not synergistic in KRAS/STK11mt/aPD1R tumors but was synergistic in KRASwt/aPD1S H1299. NPRL2 also showed a significant antitumor effect on KRASmt/aPD1R LLC2 syngeneic-tumors. The antitumor effect was correlated with increased infiltration of human cytotoxic-T, HLA-DR+DC, CD11c+DC, and downregulation of myeloid and regulatory-T cells in TME. Antitumor effect was abolished upon in-vivo depletion of CD8-T, macrophages, and CD4-T cells whereas remained unaffected upon NK-cell depletion. A distinctive protein-expression profile was found after NPRL2 treatment. IFNγ, CD8b, and TBX21 associated with T-cell functions were significantly increased, whereas FOXP3, TGFB1/B2, and IL-10RA were strongly inhibited by NPRL2. A list of T-cell co-inhibitory molecules was also downregulated. Restoration of NPRL2 exhibited significantly slower tumor growth in humanized-mice, which was associated with increased presence of human cytotoxic-T, and DC and decreased percentage of Treg, MDSC, and TAM in TME. NPRL2-stable cells showed a substantial increase in colony-formation inhibition and heightened sensitivity to carboplatin. Stable-expression of NPRL2 resulted in the downregulation of MAPK and AKT-mTOR signaling. Taken-together, NPRL2 gene-therapy induces antitumor activity on KRAS/STK11mt/aPD1R tumors through DC-mediated antigen-presentation and cytotoxic immune-cell activation.https://elifesciences.org/articles/98258nprl2 gene therapyNSCLCanti-PD1 resistanceKRAS/STK11 mutationhumanized mouse model |
| spellingShingle | Ismail M Meraz Mourad Majidi Renduo Song Feng Meng Lihui Gao Qi Wang Jing Wang Elizabeth J Shpall Jack A Roth NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic non-small cell lung cancer (NSCLC) in a humanized mouse model eLife nprl2 gene therapy NSCLC anti-PD1 resistance KRAS/STK11 mutation humanized mouse model |
| title | NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic non-small cell lung cancer (NSCLC) in a humanized mouse model |
| title_full | NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic non-small cell lung cancer (NSCLC) in a humanized mouse model |
| title_fullStr | NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic non-small cell lung cancer (NSCLC) in a humanized mouse model |
| title_full_unstemmed | NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic non-small cell lung cancer (NSCLC) in a humanized mouse model |
| title_short | NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic non-small cell lung cancer (NSCLC) in a humanized mouse model |
| title_sort | nprl2 gene therapy induces effective antitumor immunity in kras stk11 mutant anti pd1 resistant metastatic non small cell lung cancer nsclc in a humanized mouse model |
| topic | nprl2 gene therapy NSCLC anti-PD1 resistance KRAS/STK11 mutation humanized mouse model |
| url | https://elifesciences.org/articles/98258 |
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