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In patients with advanced non-small cell lung cancer (NSCLC) LAG-3 is expressed on activated TILs and predicts resistance to PD-1 axis blockers. (15PD)

Date

09 Dec 2017

Session

Poster Discussion session

Presenters

Ila Datar

Citation

Annals of Oncology (2017) 28 (suppl_11): xi3-xi5. 10.1093/annonc/mdx710

Authors

I. Datar1, M.F. Sanmamed2, J. Choi3, J. Wang2, B.S. Henick4, T. Badri2, L.D. Mejias5, M. Lozano5, J.L. Gracia6, V. Velcheti7, R. Herbst8, I. Melero9, L. Chen2, K.A. Schalper10

Author affiliations

  • 1 Department Of Pathology, Yale University School of Medicine - Pathology, 06520 - New Haven/US
  • 2 Immunobiology, Yale University School of Medicine, New Haven/US
  • 3 Genetics, Yale University School of Medicine, New Haven/US
  • 4 Department Of Medicine, Yale University School of Medicine -, 06520 - New Haven/US
  • 5 Pathology, Clinic University of Navarra, Pamplona/ES
  • 6 Oncology, Clinic University of Navarra, Pamplona/ES
  • 7 Hematology And Oncology, Cleveland Clinic Foundation, Cleveland/US
  • 8 Medical Oncology, Yale Cancer Center-Smilow Cancer Hospital, New Haven/US
  • 9 Laboratory Of Immunology, Clinica Universitaria de Navarra, 31008 - Pamplona/ES
  • 10 Pathology And Medicine, Yale University School of Medicine, 06520 - New Haven/US
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Resources

Background

The functional role and clinical utility of measuring PD-1, LAG-3 and TIM-3 in NSCLC tumor tissue remain poorly understood even though corresponding clinical trials with blocking agents are ongoing. We analyzed the expression of these targets in association with key functional immune metrics and outcome after treatment with PD-1 axis blockers in human NSCLC.

Methods

We performed CyTOF on immune cell suspensions from 20 primary human NSCLCs to map the distribution of PD-1, LAG-3 and TIM-3 and explore their function. We analyzed RNA levels of these markers in TCGA NSCLC datasets and their association with CD4/CD8 mRNA and mutational burden. Using multiplex quantitative immunofluorescence (QIF) we measured the levels of CD3, PD-1, LAG-3 and TIM-3 in 66 pre-treatment tumor samples from NSCLC patients receiving PD-1 axis blockers in 2 independent cohorts (Cohort #1, Yale, N = 42 cases [Training set] and cohort #2, Cleveland Clinic/University of Navarra, N = 24 [Validation set].

Results

In primary NSCLCs, PD-1 was predominantly expressed on T- and NKT cells. LAG-3 expression was higher in CD8+, CD4+CD25+FOXP3+ and NKT cell subsets, but low/absent in antigen-presenting cells (APCs). TIM-3 was broadly expressed in adaptive and innate immune cells, with the highest levels in APCs. Expression of all 3 markers in T-cells was associated with lymphocyte activation (CD69/HLA-DR), effector function (Granzyme-B) and proliferation (Ki-67). LAG-3-expressing T-cells showed higher association with early activation and effector function than TILs expressing PD-1 or TIM-3. In TCGA, PD-1 and LAG-3 transcripts strongly correlated with CD8, while TIM-3 was associated with CD4 mRNA. There was limited association between the markers and tumor mutational burden. In pre-treatment specimens from both cohorts of patients treated with PD-1 blockers, elevated LAG-3 but not PD-1 or TIM-3 protein were significantly associated with shorter OS.

Conclusions

PD-1, LAG-3 and TIM-3 show variable expression and are associated with T-cell activation and effector function in NSCLC. Elevated T-cell LAG-3 in baseline tumor samples predicts primary resistance to PD-1-axis blockers.

Clinical trial identification

Legal entity responsible for the study

Kurt A. Schalper- Yale University School of Medicine

Funding

NIH/NCI, DOD-LCRP, SU2C, LCRF

Disclosure

B.S. Henick: Participated in a consulting program for Boehringer Ingelheim. I. Melero: Consultancy: BMS, Roche, Bayer, Lily, AstraZeneca, Genmab, Aliigator, Tusk; Grants: Roche, BMS, Alligator, Pfizer. K.A. Schalper: Merck, Tesaro, Takeda, Onkaido/Moderna, Navigate/Novartis, Surface Oncology, Celgene, Vasculox. All other authors have declared no conflicts of interest.

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