37P - NET-mediated radio-resistance in early-stage non-small cell lung cancer

Background

Early-stage non-small cell lung cancer (NSCLC) has a 5-year survival rate of 63%. Current standards of care include surgery in the form of lobectomy or resection and stereotactic ablative radiotherapy (SABR). However, the current limitation of SABR is the moderate rates of reoccurrence in patients receiving treatment. We hypothesize that Neutrophil Extracellular Traps (NETs) may play a role in radio-resistance by decreasing T cell infiltration and activation in the tumor microenvironment.

Methods

The SABR-Bridge cohort is comprised of patients eligible for surgery that instead received neoadjuvant SABR followed by surgery 3-6 months later due to the SARS-COV-2 Pandemic. This cohort provides the unique ability to analyze changes in the microenvironment in non-responders after radiation. In addition, we use an orthotopic model of NSCLC with LLC1 cells injected into the left lung of wildtype or PAD4KO mice. Mice were then irradiated on day 7 and the tumor microenvironment was characterized with spectral flow cytometry and immunofluorescence spectroscopy.

Results

Result show that irradiated PAD4KO mice had significant decrease in both tumor volume and burden in comparison to controls. Further PD1+ CD8+ T cell infiltration in irradiated PAD4KO mice was significantly increased in comparison to controls. Survival analysis demonstrated that irradiated PAD4KO mice the received subsequent immonotherapy treatment had significantly better OS in comparison to wildtype controls.

Conclusions

It can be concluded that NETs play a role in radio resistance through decreasing T cell infiltration in a NSCLC orthotopic setting. Further, in PAD4KO preclinical models, adjuvant immunotherapy was more effective conferring greater OS. Future implications include the use of DNase or PAD4i to potentially increase radiation induced T cell infiltration in the context of adjuvant immune checkpoint-blockade therapy (ICI) in patient settings.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

CIHR.

Disclosure

All authors have declared no conflicts of interest.