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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Murine models of NSCLC with distinct driver mutations (\n                      <jats:italic>\n                        Kras\n                        <jats:sup>G12D<\/jats:sup>\n                        \/P53\n                        <jats:sup>+\/-<\/jats:sup>\n                        \/Lkb1\n                        <jats:sup>-\/-<\/jats:sup>\n                      <\/jats:italic>\n                      (KPL);\n                      <jats:italic>\n                        Kras\n                        <jats:sup>G12D<\/jats:sup>\n                        \/P53\n                        <jats:sup>+\/-<\/jats:sup>\n                      <\/jats:italic>\n                      (KP); and\n                      <jats:italic>\n                        Kras\n                        <jats:sup>G12D<\/jats:sup>\n                      <\/jats:italic>\n                      (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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2023-006896","type":"journal-article","created":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T01:45:22Z","timestamp":1695174322000},"page":"e006896","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":37,"title":["CCL21-DC in situ vaccination in murine NSCLC overcomes resistance to immunotherapy and generates systemic tumor-specific immunity"],"prefix":"10.1136","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1543-5421","authenticated-orcid":false,"given":"Ramin","family":"Salehi-Rad","sequence":"first","affiliation":[{"name":"Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA"},{"name":"Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA, 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