DNA damage repair gene mutations and their association with tumor immune regulatory gene expression in muscle invasive bladder cancer subtypes

Abstract

Background Molecular subtyping of urothelial cancer (UC) has significantly advanced the understanding of bladder tumor heterogeneity and development of prognostic and predictive biomarkers. Evolving evidence across cancers strongly suggests that tumor immunoediting has a profound impact on the behaviour of cancer cells and their adaptation to the co-evolving microenvironment and response to treatment. In alignment with these concepts, recent immune checkpoint blockade (ICB) therapies in UC have demonstrated the predictive potential of mutations in the DNA damage repair (DDR) genes. A comprehensive understanding of DDR gene inactivation associated expression of immune regulatory genes could thus aid in expansion of current immunotherapies and predictive biomarkers for the design of patient-tailored combination treatments. Methods We investigated pre-treatment tumor transcriptomic profiles of the five recently described molecular subtypes of muscle invasive urothelial cancer (MIUC; n = 408) from The Cancer Genome Atlas, to determine subtype specific immune cell abundance, expression of 67 immune regulatory genes, and association with DDR gene inactivation (via mutation, copy number alteration) profiles. Results Analysis using CIBERSORT immune cell abundance determination tool showed significant differences in immune cell profiles and abundance between MIUC subtypes. Expression patterns of a selected panel of 67 genes including both immune stimulatory and inhibitory genes, showed significant associations with subtypes, and DDR gene mutation status. Conclusion Findings from our study provide compelling evidence for co-expression of multiple immune checkpoint genes including, PD-1 , PD-L1, IDO1, TIGIT, TIM-3, TGFB1, LAG3, and others, that potentially contribute to compensatory immune evasion in bladder tumors. Our findings also emphasize the urgent need for biomarker discovery approaches that combine molecular subtype, DDR gene mutation status, tumor immune landscape classification, and immune checkpoint gene expression to increase the number of patients responding to immunotherapies. Electronic supplementary material The online version of this article (10.1186/s40425-019-0619-8) contains supplementary material, which is available to authorized users.

Association between DNA damage repair gene somatic mutations and immune‐related gene expression in ovarian cancer

“…DDR mutations were also associated with the activation of IL6‐JAK‐STAT3 pathway. One previous study has shown that DDR deficiency did not exhibit a significantly higher level of immune cells in bladder cancer . Similarly, we did not identify a significantly higher level of abundance in 22 immune cell types calculated by CIBERSORT.…”

“…One previous study has shown that DDR deficiency did not exhibit a significantly higher level of immune cells in bladder cancer. 21 Similarly, we did not identify a significantly higher level of abundance in 22 immune cell types calculated by CIBERSORT. Paradoxically, an increased Th1 cell level was observed in OvCa with DDR mutation, which indicated an immunologically hot state.…”

“…Previous studies have also illustrated the interaction of DDR with immune system, and immune‐related genes such as GZMA may also have an impact on the function of DDR system . A recent study has revealed that biallelic inactivation of DDR gene mutations exhibits decreased expression of immune regulatory gene in bladder cancer . Furthermore, DDR inactivation was associated with higher levels of TMB without a higher tumor‐infiltrating immune cell abundance in bladder cancer …”

“…A recent study has revealed that biallelic inactivation of DDR gene mutations exhibits decreased expression of immune regulatory gene in bladder cancer . Furthermore, DDR inactivation was associated with higher levels of TMB without a higher tumor‐infiltrating immune cell abundance in bladder cancer …”

“…21 Furthermore, DDR inactivation was associated with higher levels of TMB without a higher tumor-infiltrating immune cell abundance in bladder cancer. 21 However, a comprehensive view of DDR mutation-associated immunogenicity in OvCa is still unclear. We hypothesize that DDR mutations may exhibit a distinct immune profile in OvCa.…”