The immune suppressive tumor microenvironment (TME) has limited the response rate of Immune checkpoint blockade (ICB) therapy. Lack of immune stimulatory ?danger? signal molecules in TME can be a major factor contributing to resistance to tumor immunotherapy. Therefore, reprogramming the TME by over-expression of alarmin represents a novel and promising tumor immunotherapy. We have found that IL-33, which is a ?danger? signal, is expressed in normal lung epithelial cells but drastically down-regulated in human malignant lung cancer cells. Our bioinformatics analysis of the TCGA data has suggested that loss of tumor protein p53 (TP53) is responsible for IL-33 down-regulation in epithelial cells during tumorigenesis of multiple human cancers. In addition, IL-33 expression was reduced in p53 deficient compared to p53 WT murine lung tumor cells. These data suggest that down-regulation of IL-33 is a major mechanism of tumor immune evasion. Using mouse tumor models, we demonstrated that IL-33 was highly expressed in immunogenic murine tumor cells and its level could be further increased during ICB tumor therapy. Importantly, we showed that the ST2/IL-33R signaling was required for therapeutic effect of ICB therapy. Furthermore, we showed that tumor tissue expression of IL-33 synergized with both chemotherapy and ICB in inhibiting lung tumor growth. And the increased therapeutic efficacy was associated with increases in function and number of CD103+CD8+ T cells as well as decreases in Treg. We hypothesize that a novel immunotherapy based on reprogramming TME by ?alarmin? IL-33 synergizes with chemotherapy and ICB immunotherapy through promoting tumoral CD103+CD8+ T cells. SA1. Test the hypothesis that loss of the tumor suppressor gene p53 causes the down- regulation of epithelial IL-33 expression, leading to reduced tumor immune surveillance of lung tumor and accelerated lung tumor progression. SA2. We will focus on development of an improved therapy that is based on codelivery of IL-33 expressing plasmid and paclitaxel (PTX), alone or in combination with either PD1 mAbs or CTLA-4 mAbs-based ICB.

Public Health Relevance

Cancer immunotherapy has been shown recently to be a promising modality of cancer therapy. Current proposal is aim to boost antitumor immunity by delivering a potent antitumor cytokine IL-33 to cancer tissues.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA239716-01A1
Application #
9839745
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Welch, Anthony R
Project Start
2019-07-01
Project End
2024-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15260