Abstract
Immunotherapy is effective in head and neck squamous cell carcinoma (HNSCC), but only a minority of patients responds to immune checkpoint blockade (ICB). To contribute to a better understanding of the underlying immune biology, we combined histomorphological evaluation and molecular analysis of the HNSCC immune microenvironment in the TCGA cohort. Analyzing digital HE-stained slides, a method for classification of tumor infiltrating lymphocytes (TILs) in the intra-epithelial compartment (ieTILs, present vs. absent) and the stromal compartment (strTILs, high vs. low) was established. We also analyzed the abundance of eight immune cell populations (estimated from RNAseq data) and PD-L1 mRNA expression. Status of ieTILs and status of strTILs were concordant for 61%, but discordant for 39% of tumors. In univariate survival analysis, ieTILs were a positive prognostic marker for DFS in the study cohort (HR = 0.66, p = 0.015) and in the HPV− subcohort (HR = 0.68, p = 0.04), but not in the HPV + subcohort. T cells were a positive prognostic marker for DFS in the study cohort (HR = 0.80, p = 0.03) and in the HPV + subcohort (HR = 0.20, p = 0.001), but not in the HPV− subcohort. In univariate survival analysis, PD-L1 mRNA expression was neither associated with DFS nor with OS. However, in bivariate and multivariate analyses including both PD-L1 mRNA levels and T cells, PD-L1 was a negative prognostic marker of DFS and OS, while T cells remained a positive prognostic marker. In conclusion, ieTILs and strTILs were non-redundant biomarkers in HNSCC and should be evaluated separately. The identified prognostic markers should be evaluated for predictivity in ICB-treated patients.
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Abbreviations
- CTLA4:
-
Cytotoxic T-lymphocyte associated protein 4
- DFS:
-
Disease-free survival
- HNSCC:
-
Head and neck squamous cell carcinoma
- HR:
-
Hazard ratio
- ieTILs:
-
Intra-epithelial TILs
- MATH:
-
Mutant allele tumor heterogeneity
- OS:
-
Overall survival
- PD1:
-
Programmed cell death 1, official gene symbol: PDCD1
- PD-L1:
-
Programmed cell death 1 ligand 1, official gene symbol: CD274
- strTILs:
-
Stromal TILs
- TILs:
-
Tumor infiltrating lymphocytes
- TMB:
-
Tumor mutational burden
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This work was partly funded by the German Cancer Consortium (DKTK).
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JB conceived the study. MB and JB developed the statistical analysis plan. IT and CD contributed the statistical analysis plan. MB and KJ analyzed the images of the histopathological slides. MB and JB analyzed the data. All authors contributed to discussion of the data. MB and JB wrote the manuscript. All authors commented on the manuscript and approved its final version.
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W. Weichert received consultant/advisory board as well as speaker’s honoraria from Roche, Merck Sharp & Dohme (MSD), Bristol-Myers Squibb (BMS), AstraZeneca, Pfizer, Merck, Lilly, Boehringer, Novartis and Takeda. He received research funding from Roche, MSD, BMS and Bruker. C. Denkert received consultant/advisory board honoraria from MSD, Amgen and Daiichi Sankyo as well as speaker’s honoraria from Teva, Novartis, Pfizer, Roche and Amgen. He has stock and other ownership interests concerning Sividon Diagnostics. P. Schirmacher received consultant/advisory board honoraria from Pfizer, Roche, Novartis and AstraZeneca as well as speaker’s honoraria and research funding from Roche, AstraZeneca and Novartis. A. Stenzinger received consultant/advisory board honoraria from AstraZeneca, BMS, Novartis, Thermo Fisher Scientific and Illumina as well as speaker’s honoraria from BMS, MSD, Roche, Illumina, AstraZeneca, Novartis and Thermo Fisher as well as research funding from Chugai and BMS. The authors declare that there are no other conflicts of interest.
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Badr, M., Jöhrens, K., Allgäuer, M. et al. Morphomolecular analysis of the immune tumor microenvironment in human head and neck cancer. Cancer Immunol Immunother 68, 1443–1454 (2019). https://doi.org/10.1007/s00262-019-02378-w
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DOI: https://doi.org/10.1007/s00262-019-02378-w