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

Abstract

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.

Beyond Tumor Mutation Burden: Tumor Neoantigen Burden as a Biomarker for Immunotherapy and Other Types of Therapy

“…A significant dose-response association of smoking history with genetic alterations has been noted in advanced non-small-cell lung adenocarcinoma with regards to cancer-associated pathways and their corresponding mutant antigens ( 52 , 53 ). Ultraviolet stimulation is the main factor leading to high TNB in melanoma ( 54 ). In other common cancer types, such as colorectal or endometrial cancer, which harbor DNA polymerase epsilon mutations, increased TNB is attributed to endogenous mutations ( 55 , 56 ).…”

Sex-biasedZRSR2mutations in myeloid malignancies impair plasmacytoid dendritic cell activation and apoptosis

“…ICB is only modestly active in other myeloid malignancies [50] but the cancers tested (AML, MDS) do not have a UV signature. In contrast, UV signatures predict response to checkpoint blockade in solid tumors, possibly due to qualitative differences in tumor neoantigens [51]. Furthermore, PD-L1 protein is expressed in approximately half of BPDCNs [52], which also supports clinical evaluation of ICB via PD-1/PD-L1 in the disease.…”

Somatic mutational landscapes of adherens junctions and their functional consequences in cutaneous melanoma development

“…A recent study indicated increased hydrophobicity of UV-derived mutations that can enhance antigen presentation on the MHC complexes with stronger neo-antigen potentials 76 . Since most of detected CDH mutations in melanoma are highly relevant to UV exposure, CDH mutations should play certain key roles in triggering anti-tumor immunity in patients.…”