CCL21-DC in situ vaccination in murine NSCLC overcomes resistance to immunotherapy and generates systemic tumor-specific immunity
Background Despite recent advances in immunotherapy, many patients with non-small cell lung cancer (NSCLC) do not respond to immune checkpoint inhibitors (ICI). Resistance to ICI may be driven by suboptimal priming of antitumor T lymphocytes due to poor antigen presentation as well as their exclusio...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-09-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/9/e006896.full |
| _version_ | 1797669527203348480 |
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| author | Bin Liu Rui Li Edward B Garon Steven M Dubinett Kostyantyn Krysan Tianhao Zhang Aaron E Lisberg Ramin Salehi-Rad Raymond J Lim Yushen Du Linh M Tran Stephanie L Ong Zi Ling Huang Camelia Dumitras Stacy J Park William Crosson Bitta Kahangi Jensen Abascal Christopher Seet Michael Oh Maryam Shabihkhani Manash Paul |
| author_facet | Bin Liu Rui Li Edward B Garon Steven M Dubinett Kostyantyn Krysan Tianhao Zhang Aaron E Lisberg Ramin Salehi-Rad Raymond J Lim Yushen Du Linh M Tran Stephanie L Ong Zi Ling Huang Camelia Dumitras Stacy J Park William Crosson Bitta Kahangi Jensen Abascal Christopher Seet Michael Oh Maryam Shabihkhani Manash Paul |
| author_sort | Bin Liu |
| collection | DOAJ |
| description | Background Despite recent advances in immunotherapy, many patients with non-small cell lung cancer (NSCLC) do not respond to immune checkpoint inhibitors (ICI). Resistance to ICI may be driven by suboptimal priming of antitumor T lymphocytes due to poor antigen presentation as well as their exclusion and impairment by the immunosuppressive tumor microenvironment (TME). In a recent phase I trial in patients with NSCLC, in situ vaccination (ISV) with dendritic cells engineered to secrete CCL21 (CCL21-DC), a chemokine that facilitates the recruitment of T cells and DC, promoted T lymphocyte tumor infiltration and PD-L1 upregulation.Methods Murine models of NSCLC with distinct driver mutations (KrasG12D/P53+/-/Lkb1-/- (KPL); KrasG12D/P53+/- (KP); and KrasG12D (K)) and varying tumor mutational burden were used to evaluate the efficacy of combination therapy with CCL21-DC ISV plus ICI. Comprehensive analyses of longitudinal preclinical samples by flow cytometry, single cell RNA-sequencing (scRNA-seq) and whole-exome sequencing were performed to assess mechanisms of combination therapy.Results ISV with CCL21-DC sensitized immune-resistant murine NSCLCs to ICI and led to the establishment of tumor-specific immune memory. Immunophenotyping revealed that CCL21-DC obliterated tumor-promoting neutrophils, promoted sustained infiltration of CD8 cytolytic and CD4 Th1 lymphocytes and enriched progenitor T cells in the TME. Addition of ICI to CCL21-DC further enhanced the expansion and effector function of T cells both locally and systemically. Longitudinal evaluation of tumor mutation profiles revealed that CCL21-DC plus ICI induced immunoediting of tumor subclones, consistent with the broadening of tumor-specific T cell responses.Conclusions CCL21-DC ISV synergizes with anti-PD-1 to eradicate murine NSCLC. Our data support the clinical application of CCL21-DC ISV in combination with checkpoint inhibition for patients with NSCLC. |
| first_indexed | 2024-03-11T20:45:42Z |
| format | Article |
| id | doaj.art-bf2a559715ab4836a9534c935ea67e88 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-11T20:45:42Z |
| publishDate | 2023-09-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-bf2a559715ab4836a9534c935ea67e882023-10-01T16:05:06ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-09-0111910.1136/jitc-2023-006896CCL21-DC in situ vaccination in murine NSCLC overcomes resistance to immunotherapy and generates systemic tumor-specific immunityBin Liu0Rui Li1Edward B Garon2Steven M Dubinett3Kostyantyn Krysan4Tianhao Zhang5Aaron E Lisberg6Ramin Salehi-Rad7Raymond J Lim8Yushen Du9Linh M Tran10Stephanie L Ong11Zi Ling Huang12Camelia Dumitras13Stacy J Park14William Crosson15Bitta Kahangi16Jensen Abascal17Christopher Seet18Michael Oh19Maryam Shabihkhani20Manash Paul21Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAElectrical Engineering and Computer Science, Vanderbilt University, Nashville, Tennessee, USAMedicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAMedicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAMedicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAMolecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAMedicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAMedicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAMolecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAMolecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAMedicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAMedicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAMedicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAMedicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAMedicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAMolecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAMedicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAMedicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAMedicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAMedicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAPathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USAMedicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USABackground Despite recent advances in immunotherapy, many patients with non-small cell lung cancer (NSCLC) do not respond to immune checkpoint inhibitors (ICI). Resistance to ICI may be driven by suboptimal priming of antitumor T lymphocytes due to poor antigen presentation as well as their exclusion and impairment by the immunosuppressive tumor microenvironment (TME). In a recent phase I trial in patients with NSCLC, in situ vaccination (ISV) with dendritic cells engineered to secrete CCL21 (CCL21-DC), a chemokine that facilitates the recruitment of T cells and DC, promoted T lymphocyte tumor infiltration and PD-L1 upregulation.Methods Murine models of NSCLC with distinct driver mutations (KrasG12D/P53+/-/Lkb1-/- (KPL); KrasG12D/P53+/- (KP); and KrasG12D (K)) and varying tumor mutational burden were used to evaluate the efficacy of combination therapy with CCL21-DC ISV plus ICI. Comprehensive analyses of longitudinal preclinical samples by flow cytometry, single cell RNA-sequencing (scRNA-seq) and whole-exome sequencing were performed to assess mechanisms of combination therapy.Results ISV with CCL21-DC sensitized immune-resistant murine NSCLCs to ICI and led to the establishment of tumor-specific immune memory. Immunophenotyping revealed that CCL21-DC obliterated tumor-promoting neutrophils, promoted sustained infiltration of CD8 cytolytic and CD4 Th1 lymphocytes and enriched progenitor T cells in the TME. Addition of ICI to CCL21-DC further enhanced the expansion and effector function of T cells both locally and systemically. Longitudinal evaluation of tumor mutation profiles revealed that CCL21-DC plus ICI induced immunoediting of tumor subclones, consistent with the broadening of tumor-specific T cell responses.Conclusions CCL21-DC ISV synergizes with anti-PD-1 to eradicate murine NSCLC. Our data support the clinical application of CCL21-DC ISV in combination with checkpoint inhibition for patients with NSCLC.https://jitc.bmj.com/content/11/9/e006896.full |
| spellingShingle | Bin Liu Rui Li Edward B Garon Steven M Dubinett Kostyantyn Krysan Tianhao Zhang Aaron E Lisberg Ramin Salehi-Rad Raymond J Lim Yushen Du Linh M Tran Stephanie L Ong Zi Ling Huang Camelia Dumitras Stacy J Park William Crosson Bitta Kahangi Jensen Abascal Christopher Seet Michael Oh Maryam Shabihkhani Manash Paul CCL21-DC in situ vaccination in murine NSCLC overcomes resistance to immunotherapy and generates systemic tumor-specific immunity Journal for ImmunoTherapy of Cancer |
| title | CCL21-DC in situ vaccination in murine NSCLC overcomes resistance to immunotherapy and generates systemic tumor-specific immunity |
| title_full | CCL21-DC in situ vaccination in murine NSCLC overcomes resistance to immunotherapy and generates systemic tumor-specific immunity |
| title_fullStr | CCL21-DC in situ vaccination in murine NSCLC overcomes resistance to immunotherapy and generates systemic tumor-specific immunity |
| title_full_unstemmed | CCL21-DC in situ vaccination in murine NSCLC overcomes resistance to immunotherapy and generates systemic tumor-specific immunity |
| title_short | CCL21-DC in situ vaccination in murine NSCLC overcomes resistance to immunotherapy and generates systemic tumor-specific immunity |
| title_sort | ccl21 dc in situ vaccination in murine nsclc overcomes resistance to immunotherapy and generates systemic tumor specific immunity |
| url | https://jitc.bmj.com/content/11/9/e006896.full |
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