Research Papers:

Clinical and molecular features of innate and acquired resistance to anti-PD-1/PD-L1 therapy in lung cancer

Shalin Shah _, Kevin Wood, Brian Labadie, Brian Won, Ryan Brisson, Theodore Karrison, Thomas Hensing, Mark Kozloff, Riyue Bao, Jyoti D. Patel and Jason J. Luke

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Oncotarget. 2018; 9:4375-4384. https://doi.org/10.18632/oncotarget.23315

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Shalin Shah1,*, Kevin Wood2,*, Brian Labadie2, Brian Won2, Ryan Brisson2, Theodore Karrison3, Thomas Hensing2, Mark Kozloff2, Riyue Bao4, Jyoti D. Patel2 and Jason J. Luke2

1Department of Medicine, NorthShore University HealthSystems, Chicago, IL, USA

2Department of Medicine, University of Chicago, Chicago, IL, USA

3Department of Public Health Sciences, University of Chicago, Chicago IL, USA

4Center for Research Informatics and Department of Pediatrics, University of Chicago, Chicago, IL, USA

*These authors contributed equally to this work

Correspondence to:

Jason J. Luke, email: [email protected]

Keywords: non-small cell lung cancer; anti-PD-1/PD-L1 therapy; acquired resistance; immunotherapy; innate resistance

Received: September 04, 2017     Accepted: December 08, 2017     Published: December 15, 2017


Hypothesis: The majority of non-small cell lung cancer (NSCLC) patients treated with anti-PD-1/PD-L1 therapy develop either innate or acquired resistance. Across tumor types, the "T cell-inflamed" tumor microenvironment correlates with clinical response to immunotherapy. We hypothesize that clinical characteristics may be predictive of resistance and that "T cell-inflamed" NSCLC tumors can be identified by gene expression profiling.

Results: Of 93 patients, 36 (38.7%) had innate resistance and 57 (61.3%) had initial benefit to immunotherapy. Innate resistance was associated with non-smokers (p = 0.013), more involved disease sites (p = 0.011), more prior therapy (p = 0.001), and a lower albumin level (p = 0.014). Among patients with initial benefit, factors associated with subsequent progression-free survival included higher Karnofsky Performance Status (KPS) (p = 0.004) and lower depth of response to anti-PD-1 therapy (p = 0.003). A "T cell-inflamed" microenvironment was identified in 42% of TCGA adenocarcinoma samples versus 21.0% of squamous cell.

Discussion: Specific clinical characteristics appear to be predictive of either innate or acquired resistance to anti-PD-1/PD-L1 therapy. A "T cell-inflamed" tumor was more common in adenocarcinoma than squamous histology.

Methods: A retrospective review of NSCLC patients treated with anti-PD-1/PD-L1 monotherapy. Patients with innate resistance to anti-PD-1/PD-L1 therapy (defined as progression at first CT evaluation) were compared to patients with initial clinical benefit. Among those with initial clinical benefit, we identified prognostic factors for time to progression (acquired resistance) or death. To further corroborate our findings on limited numbers, immune gene expression profiling of all NSCLC samples from the TCGA database was also pursued.

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