Malignant cell expression of the aryl hydrocarbon receptor induces PD-L1 and immunosuppression in models of oral and lung cancer
0301 basic medicine
03 medical and health sciences
3. Good health
DOI:
10.4049/jimmunol.208.supp.178.11
Publication Date:
2023-01-02T16:54:01Z
AUTHORS (8)
ABSTRACT
Abstract
Immunotherapy has shown dramatic results in treating cancer but only in a minority of patients, so there is unmet need to understand the regulation of immune suppression in tumors. We have shown that the aryl hydrocarbon receptor (AhR) is a central player in regulating immune checkpoints in oral squamous cell carcinoma (OSCC) and may play a similar role in lung cancer. Orthotopic transplant of mouse AhR-knockout (KO) OSCC (MOC1) cells led to complete rejection of tumor formation coupled with increased T cell activation in tumor draining lymph nodes (tdLNs) and T cell signaling in tongues, whereas wild type (WT) OSCC challenge led to tumor formation and upregulation of T cell exhaustion pathways and checkpoint molecules. Similar patterns of AhR-facilitated immune protection appear in our lung cancer model. On average, mice transplanted subcutaneously with CMT167AhRKO lung adenocarcinoma cells survive up to twice as long as their WT-challenged counterparts; up to 50% of CMT167AhRKO-transplanted mice never grow tumor and also were partially protected from challenge with CMT167WT cells. CMT167WT-transplanted mice exhibited increased numbers of CD4+ and CD8+ in tdLNs and decreased T cell trafficking to tumors while the proportion of PD1+, CTLA4+ and Lag3+ CD4+ and CD8+ T cells were significantly lower in CMT167AhRKO tumors. AhRKO in both cell lines decreases PD-L1 expression by 50%, suggesting a mechanism of immune escape by WT tumors. Thus, the immunological protection following transplantation of both AhRKO CMT167 and MOC1 cells suggests downregulation of PD-L1 on malignant cells is at least partially responsible for immune enhancement in AhRKO cells and supports AhR’s potential as a viable immunotherapeutic target in at least two cancers.
Supported by grants from the NIH (R21 ES029624-01, R01 ES029136) as well as Find the Cause Breast Cancer Foundation and Johnson & Johnson Lung Cancer Initiative.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (0)
CITATIONS (0)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....