scholarly journals The developing landscape of combinatorial therapies of immune checkpoint blockade with DNA damage repair inhibitors for the treatment of breast and ovarian cancers

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lingling Zhu ◽  
Jiewei Liu ◽  
Jiang Chen ◽  
Qinghua Zhou
Keyword(s):  
Dna Damage ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Dna Damage Repair ◽  
Treatment Resistance ◽  
Immune Checkpoint Blockade ◽  
Lessons Learned ◽  
Checkpoint Blockade ◽  
Ovarian Cancers ◽  
Damage Repair

AbstractThe use of immune checkpoint blockade (ICB) using antibodies against programmed death receptor (PD)-1, PD ligand (PD-L)-1, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) has redefined the therapeutic landscape in solid tumors, including skin, lung, bladder, liver, renal, and breast tumors. However, overall response rates to ICB therapy remain limited in PD-L1-negative patients. Thus, rational and effective combination therapies will be needed to address ICB treatment resistance in these patients, as well as in PD-L1-positive patients who have progressed under ICB treatment. DNA damage repair inhibitors (DDRis) may activate T-cell responses and trigger inflammatory cytokines release and eventually immunogenic cancer cell death by amplifying DNA damage and generating immunogenic neoantigens, especially in DDR-defective tumors. DDRi may also lead to adaptive PD-L1 upregulation, providing a rationale for PD-L1/PD-1 blockade. Thus, based on preclinical evidence of efficacy and no significant overlapping toxicity, some ICB/DDRi combinations have rapidly progressed to clinical testing in breast and ovarian cancers. Here, we summarize the available clinical data on the combination of ICB with DDRi agents for treating breast and ovarian cancers and discuss the mechanisms of action and other lessons learned from translational studies conducted to date. We also review potential biomarkers to select patients most likely to respond to ICB/DDRi combination therapy.

scholarly journals KALRN Mutations Promote Anti-tumor Immunity and Immunotherapy Response in Cancer

2020 ◽  
Author(s):  
Mengyuan Li ◽  
Yuxiang Ma ◽  
You Zhong ◽  
Lei Qiang ◽  
Xiaosheng Wang
Keyword(s):  
Dna Damage ◽  
Cancer Patients ◽  
Tumor Immunity ◽  
Immune Checkpoint ◽  
Dna Damage Repair ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Immune Signatures ◽  
Damage Repair ◽  
Wide Range

ABSTRACTBackgroundKALRN (kalirin RhoGEF kinase) is mutated in a wide range of cancers. Nevertheless, the association between KALRN mutations and the pathogenesis of cancer remains unexplored. The identification of biomarkers for cancer immunotherapy response is important considering that immunotherapies show beneficial effects only in a subset of cancer patients.MethodsWe explored the correlation between KALRN mutations and anti-tumor immunity in 10 cancer cohorts from The Cancer Genome Atlas (TCGA) program by the bioinformatics approach. Moreover, we verified the findings from bioinformatics analysis by in vitro experiments. Furthermore, we explored the correlation between KALRN mutations and immunotherapy response in four cancer cohorts receiving immune checkpoint blockade therapy.ResultsWe found that anti-tumor immune signatures were stronger in KALRN-mutated than in KALRN-wildtype cancers. Moreover, KALRN mutations correlated with increased tumor mutation burden and the microsatellite instability or DNA damage repair deficiency genomic properties which may explain the elevated anti-tumor immunity in KALRN-mutated cancers. Furthermore, we found that PD-L1 expression was significantly upregulated in KALRN-mutated versus KALRN-wildtype cancers. The enhanced anti-tumor immune signatures and PD-L1 expression in KALRN-mutated cancers may favor the response to immune checkpoint blockade therapy in this cancer subtype, as evidenced in four cancer cohorts receiving anti-PD-1/PD-L1/CTLA-4 immunotherapy. We further revealed that the significant association between KALRN mutations and increased anti-tumor immunity was attributed to that KALRN mutations compromised the function of KALRN target Rho GTPases on regulating DNA damage repair pathways.ConclusionsThe KALRN mutation is a useful biomarker for predicting the response to immunotherapy in cancer patients.

scholarly journals Comutations in DNA Damage Response Pathways Serve as Potential Biomarkers for Immune Checkpoint Blockade

2018 ◽  
Vol 78 (22) ◽  
pp. 6486-6496 ◽  
Author(s):  
Zhijie Wang ◽  
Jing Zhao ◽  
Guoqiang Wang ◽  
Fan Zhang ◽  
Zemin Zhang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Damage Response ◽  
Potential Biomarkers

Deeper Insight in Metastatic Cancer progression;Epithelial-to-Mesenchymal Transition and Genomic Instability: implications on treatment resistance

2021 ◽  
Vol 21 ◽  
Author(s):  
Kenneth Omabe ◽  
Sandra Uduituma ◽  
David Igwe ◽  
Maxwell Omabe
Keyword(s):  
Dna Damage ◽  
Cancer Treatment ◽  
Epithelial To Mesenchymal Transition ◽  
Dna Damage Repair ◽  
Treatment Resistance ◽  
Therapy Resistance ◽  
Cellular Reprogramming ◽  
Repair System ◽  
Mesenchymal Transition ◽  
Damage Repair

: Therapy resistance remains the major obstacle to successful cancer treatment. Epithelial-to- mesenchymal transition [EMT], a cellular reprogramming process involved in embryogenesis and organ development and regulated by a number of transcriptional factors [EMT-TFs] such as ZEB1/2, is recognized for its role in tumor progression and metastasis. Recently, a growing body of evidence has implicated EMT in cancer therapy resistance but the actual mechanism that underlie this finding has remained elusive. For example, whether it is, the EMT states in itself or the EMT-TFs that modulates chemo or radio-resistance in cancer is still contentious. Here, we summarise the molecular mechanisms of EMT program and chemotherapeutic resistance in cancer with specific reference to DNA damage response [DDR]. We provide an insight into the molecular interplay that exist between EMT program and DNA repair machinery in cancer and how this interaction influences therapeutic response. We review conflicting studies linking EMT and drug resistance via the DNA damage repair axis. We draw scientific evidence demonstrating how several molecular signalling, including EMT-TFs work in operational harmony to induce EMT and confer stemness properties on the EMT-susceptible cells. We highlight the role of enhanced DNA damage repair system associated with EMT-derived stem cell-like states in promoting therapy resistance and suggest a multi-targeting modality in combating cancer treatment resistance.

scholarly journals BCG vaccine and COVID-19: implications for infection prophylaxis and cancer immunotherapy

2020 ◽  
Vol 8 (2) ◽  
pp. e001119 ◽  
Author(s):  
Madhuri Koti ◽  
Alvaro Morales ◽  
Charles H Graham ◽  
David Robert Siemens
Keyword(s):  
Immune Checkpoint ◽  
Critical Role ◽  
Immune Checkpoint Blockade ◽  
Lessons Learned ◽  
Checkpoint Blockade ◽  
Childhood Vaccination ◽  
Infection Prevalence ◽  
Type I ◽  
Infection Prophylaxis ◽  
Vaccination Programs

The COVID-19 pandemic has killed over 400 000 people globally. Ecological evidence indicates that countries with national universal BCG vaccination programs for tuberculosis (TB) prevention have a much lower incidence of severe COVID-19 and mortality compared with those that do not have such programs. BCG is a century old vaccine used for TB prevention via infant/childhood vaccination in lowto middle-income countries with high infection prevalence rate and is known to reduce all-cause neonatal mortality. BCG remains the standard immunotherapy treatment for patients with high-risk non-muscle invasive bladder cancer globally for more than 44 years. Several trials are, therefore, investigating BCG as a prophylactic against COVID-19 in healthcare workers and the elderly. In this commentary, we discuss the potential mechanisms that may underlie BCG associated heterologous protection with a focus on tertiary lymphoid structure (TLS) organogenesis. Given the significance of TLSs in mucosal immunity, their association with positive prognosis and response to immune checkpoint blockade with a critical role of Type I interferon (IFN-1) in inducing these, we also discuss potentiating TLS formation as a promising approach to enhance anti-tumor immunity. We propose that lessons learned from BCG immunotherapy success could be applied to not only augment such microbe-based therapeutics but also lead to similar adjunctive IFN-1 activating approaches to improve response to immune checkpoint blockade therapy in cancer.

scholarly journals KALRN mutations promote antitumor immunity and immunotherapy response in cancer

2020 ◽  
Vol 8 (2) ◽  
pp. e000293
Author(s):  
Mengyuan Li ◽  
Yuxiang Ma ◽  
You Zhong ◽  
Qian Liu ◽  
Canping Chen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Immune Checkpoint ◽  
Antitumor Immunity ◽  
Immune Checkpoint Blockade ◽  
Patients With Cancer ◽  
In Vivo Experiments ◽  
Damage Repair

Backgroundkalirin RhoGEF kinase (KALRN) is mutated in a wide range of cancers. Nevertheless, the association between KALRN mutations and the pathogenesis of cancer remains unexplored. Identification of biomarkers for cancer immunotherapy response is crucial because immunotherapies only show beneficial effects in a subset of patients with cancer.MethodsWe explored the correlation between KALRN mutations and antitumor immunity in 10 cancer cohorts from The Cancer Genome Atlas program by the bioinformatics approach. Moreover, we verified the findings from the bioinformatics analysis with in vitro and in vivo experiments. We explored the correlation between KALRN mutations and immunotherapy response in five cancer cohorts receiving immune checkpoint blockade therapy.ResultsAntitumor immune signatures were more enriched in KALRN-mutated than KALRN-wildtype cancers. Moreover, KALRN mutations displayed significant correlations with increased tumor mutation burden and the microsatellite instability or DNA damage repair deficiency genomic properties, which may explain the high antitumor immunity in KALRN-mutated cancers. Also, programmed cell death 1 ligand (PD-L1) expression was markedly upregulated in KALRN-mutated versus KALRN-wildtype cancers. The increased antitumor immune signatures and PD-L1 expression in KALRN-mutated cancers may favor the response to immune checkpoint blockade therapy in this cancer subtype, as evidenced in five cancer cohorts receiving antiprogrammed cell death protein 1 (PD-1)/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immunotherapy. Furthermore, the significant association between KALRN mutations and increased antitumor immunity was associated with the fact that KALRN mutations compromised the function of KALRN in targeting Rho GTPases for the regulation of DNA damage repair pathways. In vitro and in vivo experiments validated the association of KALRN deficiency with antitumor immunity and the response to immune checkpoint inhibitors.ConclusionsThe KALRN mutation is a useful biomarker for predicting the response to immunotherapy in patients with cancer.

Mutation of DNA damage repair genes confers an immune-privileged tumor microenvironment in colorectal cancer with a prognostic value.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4080-4080
Author(s):  
Dandan Liang ◽  
Huan Chen ◽  
Ying Yang ◽  
Guanxiong Zhang ◽  
Jiao Zhang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Immune Checkpoint ◽  
Prognostic Value ◽  
Dna Damage Repair ◽  
Cancer Center ◽  
Wild Type ◽  
Cancer Immunity ◽  
Mutational Status ◽  
Damage Repair ◽  
Significant Difference

4080 Background: Microsatellite instability high (MSI-H)/mismatch-repair-deficient (dMMR) has been proved as a validated biomarker in solid tumors receiving immune checkpoint inhibitors (ICIs). Recently, mutational status of the DNA damage repair (DDR) genes has been linked to anti-tumor immune response in bladder cancer. Therefore, it would be of great interest to unravel the implications of DDR in shaping the immune responsiveness in CRC. Methods: The genomic correlates were examined in a publicly available cohort from Memorial Sloan Kettering Cancer Center (MSK ICI cohort). To explore the associations between DDR mutation and immune features, the genomic data of The Cancer Genome Atlas (TCGA) colorectal adenocarcinoma (COADREAD) dataset was analyzed. Further, we determined DDR mutation and MSI status in a Chinese CRC cohort via a 543-gene panel sequencing. Results: First, we observed that DDR pathway was commonly mutated (21.79%) in the multi-cancer MSK ICI cohort, with the highest frequency of 36.36% in CRCs. Second, survival analysis revealed that the median overall survival (mOS) in patients with DDR mutations was significantly longer than that in the DDR wild-type subgroup, in both pan-cancer (P = 0.0008; mOS 31 vs 16 months) and CRC patients (P = 0.016; mOS 34 vs 13 months) in the MSK ICI cohort. However, in the TCGA COADREAD dataset, there was no significant difference in OS or progression free survival (PFS) between DDR mutant and DDR wild-type subgroups. These observation indicated a specific prognostic value for DDR mutation in patients with ICI treatment while not conventional treatment. Third, in the TCGA COADREAD dataset, DDR mutations were associated with increased TMB, enrichment of immune cell infiltration and immune checkpoint molecule expression, suggesting an improvement of various steps of the cancer immunity cycles in DDR mutant CRCs. Lastly, we investigated the DDR mutational pattern, and its associations with MSI-H and other genomic features in a Chinese CRC cohort. Notably, MSI-H and DDR mutation account for 5.7% and 13.4% respectively, suggesting that DDR may identify a higher proportion of potential responders than MSI-H. Conclusions: Our data suggest that DDR mutation is a potential prognostic biomarker for ICI-treated CRCs. Functional analysis in TCGA dataset revealed that DDR mutation might be an indication of enhanced cancer immunity. The higher incidence of DDR mutation in Chinese CRCs emphasized the future utility of panel-based DDR evaluation in guiding ICI treatment.

scholarly journals PARP inhibition in Ewing sarcoma: impact of germline DNA damage repair defects and activation of immunoregulatory pathways

2020 ◽  
Author(s):  
Lisa M. Maurer ◽  
Rosemarie E. Venier ◽  
Elina Mukherjee ◽  
Claire M. Julian ◽  
Jessica D. Daley ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ewing Sarcoma ◽  
Immune Checkpoint ◽  
Dna Damage Repair ◽  
Germline Mutations ◽  
Parp Inhibition ◽  
Damage Repair ◽  
The Impact ◽  
Ewing Tumor

ABSTRACTEwing sarcoma, an oncofusion-driven primary bone tumor, can occur in the setting of various germline mutations in DNA damage repair pathway genes. We recently reported our discovery of a germline mutation in the DNA damage repair protein BARD1 (BRCA1-associated RING domain-1) in a patient with Ewing sarcoma. BARD1 is recruited to the site of DNA double stranded breaks via the poly(ADP-ribose) polymerase (PARP) protein and plays a critical role in DNA damage response pathways including homologous recombination. PARP inhibitors (PARPi) are effective against Ewing sarcoma cells in vitro, though have demonstrated limited success in clinical trials to date. In order to assess the impact of BARD1 loss on Ewing sarcoma sensitivity to PARP inhibitor therapy, we generated the novel PSaRC318 patient-derived Ewing tumor cell from our patient with a germline BARD1 mutation and then analyzed the response of these cells to PARPi. We demonstrate that PSaRC318 cells are sensitive to PARP inhibition and by testing the effect of BARD1 depletion in additional Ewing sarcoma cell lines, we confirm that loss of BARD1 enhances PARPi sensitivity. In certain malignancies, DNA damage can activate the IRF1 (interferon response factor 1) immunoregulatory pathway, and the activation of this pathway can drive immunosuppression through upregulation of the immune checkpoint protein PD-L1. In order to determine the ability of PARPi to alter Ewing tumor immunoregulation, we evaluated whether PARPi results in upregulation of the IRF1-PDL1 pathway. Indeed, we now demonstrate that PARPi leads to increased PD-L1 expression in Ewing sarcoma. Together, these data thus far suggest that while Ewing tumors harboring germline mutations in DNA damage repair proteins may in respond to PARPi in vitro, in vivo benefit of PARPi may only be demonstrated when counteracting the immunosuppressive effects of DNA damage by concurrently targeting immune checkpoint proteins.

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