Journal for ImmunoTherapy of Cancer (2019-02-01)

Proliferative potential and resistance to immune checkpoint blockade in lung cancer patients

  • Sarabjot Pabla,
  • Jeffrey M. Conroy,
  • Mary K. Nesline,
  • Sean T. Glenn,
  • Antonios Papanicolau-Sengos,
  • Blake Burgher,
  • Jacob Hagen,
  • Vincent Giamo,
  • Jonathan Andreas,
  • Felicia L. Lenzo,
  • Wang Yirong,
  • Grace K. Dy,
  • Edwin Yau,
  • Amy Early,
  • Hongbin Chen,
  • Wiam Bshara,
  • Katherine G. Madden,
  • Keisuke Shirai,
  • Konstantin Dragnev,
  • Laura J. Tafe,
  • Daniele Marin,
  • Jason Zhu,
  • Jeff Clarke,
  • Matthew Labriola,
  • Shannon McCall,
  • Tian Zhang,
  • Matthew Zibelman,
  • Pooja Ghatalia,
  • Isabel Araujo-Fernandez,
  • Arun Singavi,
  • Ben George,
  • Andrew Craig MacKinnon,
  • Jonathan Thompson,
  • Rajbir Singh,
  • Robin Jacob,
  • Lynn Dressler,
  • Mark Steciuk,
  • Oliver Binns,
  • Deepa Kasuganti,
  • Neel Shah,
  • Marc Ernstoff,
  • Kunle Odunsi,
  • Razelle Kurzrock,
  • Mark Gardner,
  • Lorenzo Galluzzi,
  • Carl Morrison

Journal volume & issue
Vol. 7, no. 1
pp. 1 – 13


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Abstract Background Resistance to immune checkpoint inhibitors (ICIs) has been linked to local immunosuppression independent of major ICI targets (e.g., PD-1). Clinical experience with response prediction based on PD-L1 expression suggests that other factors influence sensitivity to ICIs in non-small cell lung cancer (NSCLC) patients. Methods Tumor specimens from 120 NSCLC patients from 10 institutions were evaluated for PD-L1 expression by immunohistochemistry, and global proliferative profile by targeted RNA-seq. Results Cell proliferation, derived from the mean expression of 10 proliferation-associated genes (namely BUB1, CCNB2, CDK1, CDKN3, FOXM1, KIAA0101, MAD2L1, MELK, MKI67, and TOP2A), was identified as a marker of response to ICIs in NSCLC. Poorly, moderately, and highly proliferative tumors were somewhat equally represented in NSCLC, with tumors with the highest PD-L1 expression being more frequently moderately proliferative as compared to lesser levels of PD-L1 expression. Proliferation status had an impact on survival in patients with both PD-L1 positive and negative tumors. There was a significant survival advantage for moderately proliferative tumors compared to their combined highly/poorly counterparts (p = 0.021). Moderately proliferative PD-L1 positive tumors had a median survival of 14.6 months that was almost twice that of PD-L1 negative highly/poorly proliferative at 7.6 months (p = 0.028). Median survival in moderately proliferative PD-L1 negative tumors at 12.6 months was comparable to that of highly/poorly proliferative PD-L1 positive tumors at 11.5 months, but in both instances less than that of moderately proliferative PD-L1 positive tumors. Similar to survival, proliferation status has impact on disease control (DC) in patients with both PD-L1 positive and negative tumors. Patients with moderately versus those with poorly or highly proliferative tumors have a superior DC rate when combined with any classification schema used to score PD-L1 as a positive result (i.e., TPS ≥ 50% or ≥ 1%), and best displayed by a DC rate for moderately proliferative tumors of no less than 40% for any classification of PD-L1 as a negative result. While there is an over representation of moderately proliferative tumors as PD-L1 expression increases this does not account for the improved survival or higher disease control rates seen in PD-L1 negative tumors. Conclusions Cell proliferation is potentially a new biomarker of response to ICIs in NSCLC and is applicable to PD-L1 negative tumors.