(1) Salehi-Rad R (2) Lim RJ (3) Du Y (4) Tran LM (5) Li R (6) Ong SL (7) Ling Huang Z (8) Dumitras C (9) Zhang T (10) Park SJ (11) Crosson W (12) Kahangi B (13) Abascal J (14) Seet C (15) Oh M (16) Shabihkhani M (17) Paul M (18) Krysan K (19) Lisberg AE (20) Garon EB (21) Liu B (22) Dubinett SM

Journal for immunotherapy of cancer

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 (Kras(G12D)/P53(+/-)/Lkb1(-/-) (KPL); Kras(G12D)/P53(+/-) (KP); and Kras(G12D) (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.

Author Info: (1) Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA. (2) Molecular and Medical Pha

Author Info: (1) Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA. (2) Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (3) Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China. (4) Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA. (5) Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (6) Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (7) Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (8) Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (9) Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (10) Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (11) Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (12) Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (13) Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (14) Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (15) Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (16) Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. (17) Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (18) Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (19) Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (20) Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (21) Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA sdubinett@mednet.ucla.edu bliu@mednet.ucla.edu. (22) Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA sdubinett@mednet.ucla.edu bliu@mednet.ucla.edu. Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.

Citation: J Immunother Cancer 2023 Sep 11: Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/37730274

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