(1) Wang J (2) Gai J (3) Zhang T (4) Niu N (5) Qi H (6) Thomas DL 2nd (7) Li K (8) Xia T (9) Rodriguez C (10) Parkinson R (11) Durham J (12) McPhaul T (13) Narang AK (14) Anders RA (15) Osipov A (16) Wang H (17) He J (18) Laheru DA (19) Herman JM (20) Lee V (21) Jaffee EM (22) Thompson ED (23) Zhu Q (24) Zheng L

Science advances

Radiotherapy is hypothesized to have an immune-modulating effect on the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) to sensitize it to anti-PD-1 antibody (a-PD-1) treatment. We collected paired pre- and posttreatment specimens from a clinical trial evaluating combination treatment with GVAX vaccine, a-PD-1, and stereotactic body radiation (SBRT) following chemotherapy for locally advanced PDACs (LAPC). With resected PDACs following different neoadjuvant therapies as comparisons, effector cells in PDACs were found to skew toward a more exhausted status in LAPCs following chemotherapy. The combination of GVAX/a-PD-1/SBRT drives TME to favor antitumor immune response including increased densities of GZMB(+)CD8(+) T cells, T(H)1, and T(H)17, which are associated with longer survival, however increases immunosuppressive M2-like tumor-associated macrophages (TAMs). Adding SBRT to GVAX/a-PD-1 shortens the distances from PD-1(+)CD8(+) T cells to tumor cells and to PD-L1(+) myeloid cells, which portends prolonged survival. These findings have guided the design of next radioimmunotherapy studies by targeting M2-like TAM in PDACs.

Author Info: (1) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of

Author Info: (1) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. (2) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (3) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (4) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (5) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Quantitative Sciences Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (6) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (7) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (8) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (9) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (10) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (11) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (12) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (13) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (14) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (15) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA. (16) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Quantitative Sciences Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (17) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (18) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (19) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Northwell Health System, New Hyde Park, NY, 11042, USA. (20) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (21) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (22) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (23) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (24) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Citation: Sci Adv 2024 Feb 9 10:eadk1827 Epub02/07/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38324679

Tags: