Despite having been approved as first and second line therapy for non-small cell lung cancer (NSCLC), anti-PD- 1 antibodies still fail in a substantial proportion of lung cancer patients. The mechanism that underlies the failure of anti-PD-1 therapy in the majority of NSCLC patients is not yet fully understood. We have discovered that, in the anti-PD-1-resistant LSL-KrasG12D murine lung adenocarcinoma mouse model, treatment induces a T-cell activation profile that favors Th17/??T17 reinvigoration over CD8+ T cell activation. In contrast, when administered in conjunction with an anti-IL-17 neutralizing antibody, anti-PD-1 treatment results in a dramatic enhancement of CD8+ T-cell cytotoxicity with near-complete eradication of established disease. These findings provide the premise for our central hypothesis that in NSCLC, the failure of anti-PD-1 is, at least in part, due to reinvigoration of PD-1+ type 17 T cells (Th17/??T17), which actively undermine anti-PD-1-mediated restoration of cytotoxic function in CD8+ T-cells.
Aim 1 studies will directly test this notion and delineate the mechanistic basis of type 17 T-cell ? cytotoxic T-lymphocyte antagonism in anti-PD-1-treated mice.
In Aim 2, we will define the ontogeny of the pro-tumorigenic PD-1+ type 17 T cells that are found in the dysplastic lung. Specifically, we will test the extended hypothesis that the PD-1+ T17 cell expansion is driven by the lung microbiota-interstitial macrophage axis; and that the microbial signature can predict anti-PD-1 responsiveness in individual LSL- KrasG12D mice. Lastly, in Aim 3, we will establish whether the lung microbiome can determine the severity of type 17 T-cell prevalence/activity in the lung and ultimately prognosticate anti-PD-1 responsiveness in NSCLC patients. The proposed study is conceptually impactful as it addresses an important clinical conundrum; is mechanistically novel; and has translational relevance since it introduces therapeutic/prognostic approaches that can rapidly move to the clinic.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
1P20GM135004-01
Application #
9854340
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Louisville
Department
Type
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292