Neoadjuvant radioimmunotherapy in pancreatic cancer enhances effector T cell infiltration and shortens their distances to tumor cells.
Fu-Yu LiJessica GaiTengyi ZhangNan NiuHanfei QiDwayne L ThomasKeyu LiTao XiaChristina RodriguezRose ParkinsonJennifer N DurhamThomas McPhaulAmol K NarangRobert A AndersArsen OsipovHao WangJin HeDaniel A LaheruJoseph M HermanValerie LeeElizabeth D ThompsonElizabeth D ThompsonQingfeng ZhuLei ZhengPublished in: Science advances (2024)
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.
Keyphrases
- locally advanced
- radiation therapy
- induced apoptosis
- rectal cancer
- immune response
- dendritic cells
- clinical trial
- lymph node
- cell cycle arrest
- signaling pathway
- squamous cell carcinoma
- radiation induced
- early stage
- acute myeloid leukemia
- randomized controlled trial
- inflammatory response
- toll like receptor
- free survival
- replacement therapy
- smoking cessation
- cell proliferation
- type iii
- double blind