Novel Insights into the Correlation Between DNA Damage Response and Immune Therapy Escape In Urinary Tumors

Immunotherapies such as chimeric antigen receptor T-cell (CAR-T) therapy and immune checkpoint blockade (ICB) therapy have been applied in clinical practice and exerted promising antitumor effects in hematological and solid tumor malignancies, including bladder cancer and lung cancer. However, the application of CART-T and ICB therapy to prostate cancer (PCa), especially metastatic castration resistant prostate cancer (mCRPC), do not belong to the successful cases. Clinical trials indicated that patients with mCRPC benefit very limitedly from either ICB or CAR-T therapy. Studies have suggested that most positive responses to ICB therapy are limited in PCa patients with mismatch repair deficiency and/or high microsatellite instability (MSI-H) tumors, or deficiency in other DNA damage repair (DDR) genes. It has been identified that DDR deficiency induced by either genetic alterations or pharmacological inhibitors could improve the responses of ICB in solid tumors, including prostate cancer. Although the mechanisms of the DDR-ICB interaction have not been fully elucidated yet, preclinical trials combining a DDR inhibitor (DDRi) with ICB showed significant additive benefits, especially in PCa patients with DDR gene deficiency. Therefore, it is of great importance to identify specific molecular biomarkers which could predict the responses to immunotherapy and identify specific subtypes of PCa patients who may benefit from immunological treatments. Moreover, whether DDR inhibitor could enhance the anti-tumor activity of ICB against other types of urinary tumors such as renal cell cancer and bladder urothelial cell cancer and the underlying mechanisms remain to be further illuminated.

The mechanisms of DDR-ICB interaction in urinary tumors remain largely unknown, and the mechanisms underlying DNA damage modulate anti-tumor immunity and reconstruction of tumor microenvironment in urinary tumors also remain elucidative. Besides, research of small molecules and recombinant inhibitors driving DNA damage response deficiency and promoting the effects of immune therapy is of great value for future treatments against urinary tumors especially prostate cancer. More importantly, revealing the gene signatures of novel prostate cancer subtype basing on transcriptome sequencing and genomic analysis is critical to identify immune therapy-sensitive patient groups. And more work still needs to be done to validate the potential anti-tumor effects of ICB alone or combined with DDR therapy against urinary tumors basing on animal models and organoid models.

We welcome contributions in form of Original Research articles, Reviews and Mini-Reviews that cover but are not limited to the following topics:

•The molecular mechanisms under DNA damage that induces immunotherapy sensitivity in urinary cancers.
•Translational studies attempting to apply DNA damage response inhibitor in combination with immune checkpoint blockage therapy to urinary cancer treatments.
•Gene signature/gene model revealing novel prostate cancer subtype which may be sensitive to immunotherapy basing on transcriptome sequencing/genomic analysis, with essential experimental validation.
•Bioinformatic analysis based on RNA sequencing/single cell sequencing to uncover the heterogeneity of prostate cancer, potential biomarkers and therapeutic targets may modulates the effects of immunotherapy in prostate cancer, with essential experimental validation.

Please note: studies consisting solely of bioinformatic investigation of publicly available genomic/transcriptomic/proteomic data do not fall within the scope of the section unless they are expanded and provide significant biological or mechanistic insight into the process being studied and will not be accepted as part of this Research Topic.