CD122-directed interleukin-2 treatment mechanisms in bladder cancer differ from αPD-L1 and include tissue-selective γδ T cell activation. Issue 4 (13th April 2021)

• Record Type: Journal Article
• Authors: Reyes, Ryan Michael; Deng, Yilun; Zhang, Deyi; Ji, Niannian; Mukherjee, Neelam; Wheeler, Karen; Gupta, Harshita B; Padron, Alvaro S; Kancharla, Aravind; Zhang, Chenghao; Garcia, Myrna; Kornepati, Anand V R; Boyman, Onur; Conejo-Garcia, Jose R; Svatek, Robert S; Curiel, Tyler J
• Is Part Of: Journal for immunotherapy of cancer. Volume 9:Issue 4(2021)
• Publication Date: 2021-04-13
• Subjects: drug evaluation -- preclinical -- immunotherapy -- lymphocyte activation -- tumor microenvironment -- urinary bladder neoplasms; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2020-002051
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: Anti-programmed death-ligand 1 (αPD-L1) immunotherapy is approved to treat bladder cancer (BC) but is effective in <30% of patients. Interleukin (IL)-2/αIL-2 complexes (IL-2c) that preferentially target IL-2 receptor β (CD122) augment CD8 + antitumor T cells known to improve αPD-L1 efficacy. We hypothesized that the tumor microenvironment, including local immune cells in primary versus metastatic BC, differentially affects immunotherapy responses and that IL-2c effects could differ from, and thus complement αPD-L1. Methods: We studied mechanisms of IL-2c and αPD-L1 efficacy using PD-L1 + mouse BC cell lines MB49 and MBT-2 in orthotopic (bladder) and metastatic (lung) sites. Results: IL-2c reduced orthotopic tumor burden and extended survival in MB49 and MBT-2 BC models, similar to αPD-L1. Using antibody-mediated cell depletions and genetically T cell-deficient mice, we unexpectedly found that CD8 + T cells were not necessary for IL-2c efficacy against tumors in bladder, whereas γδ T cells, not reported to contribute to αPD-L1 efficacy, were indispensable for IL-2c efficacy there. αPD-L1 responsiveness in bladder required conventional T cells as expected, but not γδ T cells, altogether defining distinct mechanisms for IL-2c and αPD-L1 efficacy. γδ T cells did not improve IL-2c treatment of subcutaneously challenged BC or orthotopic (peritoneal) ovarian cancer, consistent with tissue-specific and/or tumor-specific γδ T cell contributions to IL-2c efficacy. IL-2c significantly altered bladder intratumoral γδ T cell content, activation status, and specific γδ T cell subsets with antitumor or protumor effector functions. Neither IL-2c nor αPD-L1 alone treated lung metastatic MB49 or MBT-2 BC, but their combination improved survival in both models. Combination treatment efficacy in lungs required CD8 + T cells but not γδ T cells. Conclusions: Mechanistic insights into differential IL-2c and αPD-L1 treatment and tissue-dependent effects could help develop rational combination treatment strategies to improve treatment efficacy in distinct cancers. These studies also provide insights into γδ T cell contributions to immunotherapy in bladder and engagement of adaptive immunity by IL-2c plus αPD-L1 to treat refractory lung metastases.