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Mutation patterns in genes encoding interferon signaling and antigen presentation: A pan-cancer survey with
Jan Budczies1,2, Michael Bockmayr1,3, Frederick Klauschen1,2
1Institute of Pathology, Charité University Hospital, Berlin, Germany.
Abstract:
Blockade of immune checkpoints has become a powerful tool in cancer medicine, which is effective across various solid cancer types and hematologic malignancies. While immunohistochemical detection of PD-L1 expression in tumor cells, immune cells, or both has been introduced as predictive biomarker in several clinical trials, shortcomings and limitations of this approach were quickly recognized. As a single biomarker is unlikely to adequately reflect the complex interplay between immune cells and cancer, various genetic determinants of therapy success, including microsatellite instability, mutational burden, and PD-L1 amplification, are being investigated. Very recent work indicates that mutations in B2M, JAK1, and JAK2 render melanoma resistant to immune checkpoint blockade, thus serving as negative response predictors. Using the TCGA dataset, we performed a pan-cancer analysis of potentially damaging mutations in key genes implicated in antigen presentation and interferon-gamma signaling and investigated associations with transcript levels of immune checkpoint genes, cytolytic activity, and mutational burden. For B2M, JAK1, and JAK2, we observed overall mutation frequencies of 1.8%, 2%, and 2.6%, respectively, and found significant associations with mutational burden. On pathway level, melanoma as well as bladder, gastric, and lung cancer were most frequently affected by putative resistance mutations with mutation rates of 27%-50% in the antigen presentation pathway and of 16%-21% in the interferon signaling pathway. Our analysis suggests that a significant number of tumors harbor mutations that may negatively interfere with immune checkpoint inhibition, or confer a higher likelihood of resistance for which a second hit is ultimately required. Since these mutations are prevalent in treatment-naïve tumors, genetic screening prior to therapy might complement current approaches at predicting response to immune checkpoint blockade.
Insights
Genetic mutations in key cancer immunity genes like B2M, JAK1, and JAK2 can predict resistance to immune checkpoint blockade therapy. Pre-treatment genetic screening may improve patient selection for these powerful cancer treatments.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Immune checkpoint blockade is a vital cancer therapy, but response prediction remains challenging.
- Current biomarkers like PD-L1 have limitations.
- Genetic factors influencing therapy response are under investigation.
Purpose of the Study:
- To conduct a pan-cancer analysis of mutations in genes related to antigen presentation and interferon-gamma signaling.
- To assess the association of these mutations with immune checkpoint gene expression, cytolytic activity, and mutational burden.
- To identify genetic predictors of resistance to immune checkpoint blockade therapy.
Main Methods:
- Utilized The Cancer Genome Atlas (TCGA) dataset for analysis.
- Performed a pan-cancer analysis of mutations in genes critical for antigen presentation and interferon-gamma signaling.
- Investigated associations between mutations, immune gene expression, cytolytic activity, and mutational burden.
Main Results:
- Identified mutation frequencies for B2M (1.8%), JAK1 (2%), and JAK2 (2.6%), with significant associations with mutational burden.
- Melanoma, bladder, gastric, and lung cancers showed high rates of resistance mutations (27%-50% in antigen presentation, 16%-21% in interferon signaling pathways).
- A substantial proportion of tumors harbor mutations potentially conferring resistance to immune checkpoint inhibitors.
Conclusions:
- Mutations in B2M, JAK1, and JAK2 are associated with resistance to immune checkpoint blockade.
- These mutations are prevalent even in treatment-naïve tumors.
- Pre-therapy genetic screening could enhance the prediction of patient response to immune checkpoint blockade.
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