Clinical and Molecular Heterogeneity in Patients with Innate Resistance to Anti-PD-1 +/− Anti-CTLA-4 Immunotherapy in Metastatic Melanoma Reveals Distinct Therapeutic Targets
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patient and Sample Selection
2.2. Assessment of TILs Based on Haematoxylin and Eosin (H&E) Staining
2.3. Targeted RNA Sequencing Library Preparation and Sequencing
2.4. Targeted Gene Expression Analysis
2.5. Hierarchical Clustering Analysis of Gene Expression Profiles
2.6. Gene Set Enrichment Analysis (GSEA)
2.7. Multiplex Immunohistochemistry (mIHC)
2.8. Multispectral Image Analysis
2.9. Statistical Analysis
3. Results
3.1. Patient Characteristics
3.2. Clinical Characteristics of Patients with Different Patterns of Progression
3.3. Rapid Progressors Have Lower Expression of TILs and CD68+ Macrophages Compared to Patients Who Progressed after 2 Months
3.4. Differential Expression Analysis Identifies Two Distinct Groups of Non-Responders to Anti-PD-1-Based Therapies
3.5. Heterogeneous Expression of Immune Drug Targets within Non-Responders to Anti-PD-1-Based Therapies
3.6. Drug Target Profiles of Non-Responders Are Associated with TIL Expression and the DEG Clusters
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Number of Patients, n (%) | 40 (100) |
---|---|
Age median (range) | 67 (34–96) |
Sex, n (%) Male | 26 (65) |
ECOG, n (%) >=1 | 19 (48) |
Mutational Status, n (%) BRAF-Mutant V600E Other NRAS-Mutant WT 1 | 5 (13) 4 (10) 13 (33) 18 (45) |
LDH, n (%) >ULN | 15 (38) |
AJCC v8 2, n (%) IIIc/M1a/M1b M1c M1d | 16 (40) 12 (30) 12 (30) |
Liver Metastases, n (%) | 11 (28) |
Treatment, n (%) Anti-PD-1 Anti-CTLA-4 + Anti-PD-1 | 26 (65) 14 (35) |
Toxicity, n (%) Any ≥G3 | 8 (20) |
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Gide, T.N.; Pires da Silva, I.; Quek, C.; Ferguson, P.M.; Batten, M.; Shang, P.; Ahmed, T.; Menzies, A.M.; Carlino, M.S.; Saw, R.P.M.; et al. Clinical and Molecular Heterogeneity in Patients with Innate Resistance to Anti-PD-1 +/− Anti-CTLA-4 Immunotherapy in Metastatic Melanoma Reveals Distinct Therapeutic Targets. Cancers 2021, 13, 3186. https://doi.org/10.3390/cancers13133186
Gide TN, Pires da Silva I, Quek C, Ferguson PM, Batten M, Shang P, Ahmed T, Menzies AM, Carlino MS, Saw RPM, et al. Clinical and Molecular Heterogeneity in Patients with Innate Resistance to Anti-PD-1 +/− Anti-CTLA-4 Immunotherapy in Metastatic Melanoma Reveals Distinct Therapeutic Targets. Cancers. 2021; 13(13):3186. https://doi.org/10.3390/cancers13133186
Chicago/Turabian StyleGide, Tuba N., Inês Pires da Silva, Camelia Quek, Peter M. Ferguson, Marcel Batten, Ping Shang, Tasnia Ahmed, Alexander M. Menzies, Matteo S. Carlino, Robyn P. M. Saw, and et al. 2021. "Clinical and Molecular Heterogeneity in Patients with Innate Resistance to Anti-PD-1 +/− Anti-CTLA-4 Immunotherapy in Metastatic Melanoma Reveals Distinct Therapeutic Targets" Cancers 13, no. 13: 3186. https://doi.org/10.3390/cancers13133186
APA StyleGide, T. N., Pires da Silva, I., Quek, C., Ferguson, P. M., Batten, M., Shang, P., Ahmed, T., Menzies, A. M., Carlino, M. S., Saw, R. P. M., Thompson, J. F., Scolyer, R. A., Long, G. V., & Wilmott, J. S. (2021). Clinical and Molecular Heterogeneity in Patients with Innate Resistance to Anti-PD-1 +/− Anti-CTLA-4 Immunotherapy in Metastatic Melanoma Reveals Distinct Therapeutic Targets. Cancers, 13(13), 3186. https://doi.org/10.3390/cancers13133186