Role of ultraviolet mutational signature versus tumor mutation burden in predicting response to immunotherapy

Autor: Paul Riviere, Amélie Boichard, Pablo Tamayo, Razelle Kurzrock, Timothy V. Pham, Huwate Yeerna, Aaron M. Goodman
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Male
Cancer Research
Ultraviolet Rays
medicine.medical_treatment
Kaplan-Meier Estimate
Major histocompatibility complex
lcsh:RC254-282
UV mutational signature
03 medical and health sciences
0302 clinical medicine
Immune system
Antigens
Neoplasm
Genetics
medicine
Humans
In patient
Exome
Amino Acids
Research Articles
biology
business.industry
Genome
Human
Immunogenicity
Melanoma
General Medicine
Immunotherapy
Middle Aged
medicine.disease
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Progression-Free Survival
Blockade
Tumor Burden
Immune recognition
030104 developmental biology
Oncology
Mutagenesis
030220 oncology & carcinogenesis
Multivariate Analysis
Mutation
biology.protein
Cancer research
Molecular Medicine
checkpoint blockade
Female
immunotherapy
business
Hydrophobic and Hydrophilic Interactions
Research Article
Zdroj: Molecular Oncology, Vol 14, Iss 8, Pp 1680-1694 (2020)
Molecular Oncology
ISSN: 1574-7891
1878-0261
Popis: Hydrophobic neoantigens are more immunogenic because they are better presented by the major histocompatibility complex and better recognized by T cells. Tumor cells can evade the immune response by expressing checkpoints such as programmed death ligand 1. Checkpoint blockade reactivates immune recognition and can be effective in diseases such as melanoma, which harbors a high tumor mutational burden (TMB). Cancers presenting low or intermediate TMB can also respond to checkpoint blockade, albeit less frequently, suggesting the need for biological markers predicting response. We calculated the hydrophobicity of neopeptides produced by probabilistic in silico simulation of the genomic UV exposure mutational signature. We also computed the hydrophobicity of potential neopeptides and extent of UV exposure based on the UV mutational signature enrichment (UVMSE) score in The Cancer Genome Atlas (TCGA; N = 3543 tumors), and in our cohort of 151 immunotherapy‐treated patients. In silico simulation showed that UV exposure significantly increased hydrophobicity of neopeptides, especially over multiple mutagenic cycles. There was also a strong correlation (R 2 = 0.953) between weighted UVMSE and hydrophobicity of neopeptides in TCGA melanoma patients. Importantly, UVMSE was able to predict better response (P = 0.0026), progression‐free survival (P = 0.036), and overall survival (P = 0.052) after immunotherapy in patients with low/intermediate TMB, but not in patients with high TMB. We show that higher UVMSE scores could be a useful predictor of better immunotherapy outcome, especially in patients with low/intermediate TMB, likely due to increased hydrophobicity (and hence immunogenicity) of neopeptides.
The mutational pattern induced by ultraviolet radiation changes the exome to encode for more hydrophobic antigens. When these more lipophilic antigens are presented on the cell surface to T cells by major histocompatibility complex I molecules, they could induce a stronger immune response. This was demonstrated in a cohort of 151 patients from the Moores Cancer Center, particularly in the low TMB subset.
Databáze: OpenAIRE
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