Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity

Ma, Xiaoxiao; Riaz, Nadeem; Samstein, Robert M.; Lee, Mark; Makarov, Vladimir; Valero, Cristina; Chowell, Diego; Kuo, Fengshen; Hoen, Douglas R.; Fitzgerald, Conall; Jiang, Hui; Alektiar, Jonathan; Alban, Tyler J.; Jurić, Ivan; Parthasarathy, Prerana Bangalore; Zhao, Yu; Sabio, Erich; Verma, Richa; Srivastava, Raghvendra M.; Vuong, Lynda; Yang, Wei; Zhang, Xiao; Wang, Jingming; Chu, Lawrence K; Wang, Stephen L; Kelly, Daniel; Pei, Xin; Chen, Jiapeng; Yaeger, Rona; Zamarin, Dmitriy; Zehir, Ahmet; Gönen, Mithat; Morris, Luc G.T.; Chan, Timothy A.

doi:10.1038/s41588-022-01108-w

Cited by 39 publications

(30 citation statements)

References 92 publications

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“…In addition, two pediatric patients with biallelic dMMR recurrent GBMs who exhibited exceptional and long-lasting responses to nivolumab harbored driver POLE mutations in their tumors (55). This is consistent with POLE mutations producing a distinct mutational signature based on the induction of specific patterns of nucleotide substitutions that generate neopeptides with increased hydrophobicity that are associated with response to ICB (50,56). Notably, 35% of de novo hypermutated gliomas are associated with deficiencies in POLE (57), but this association is found in only 1% to 2% of all GBM tumors.…”

Section: R E I E W S E R I E S : I M M U N E E N V I R O N M E N T I ...supporting

confidence: 61%

Immune checkpoint blockade in glioblastoma: from tumor heterogeneity to personalized treatment

Arrieta¹,

Dmello²,

McGrail³

et al. 2023

Journal of Clinical Investigation

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Conflict of interest: VAA and AMS are authors of a patent filed by Northwestern University related to predicting the response to immunotherapy in gliomas (US2021071138). AMS has received in-kind and/or funding support for research from Agenus, Bristol Myers Squibb, and Carthera. RS has acted or is acting as a scientific advisor or has served on advisory boards for Alpheus Medical (formerly Craniovation), AstraZeneca, Boston Scientific, Carthera, Celularity, GT Medical, Insightech, Lockwood (BlackDiamond), Northwest Biotherapeutics, Novocure, Syneos Health (Boston Biomedical), TriAct Therapeutics, and Varian Medical Systems. ABH serves on the advisory board of Caris Life Sciences and the WCG Oncology Advisory Board; receives royalty and milestone payments from DNAtrix for the licensing of "Biomarkers and combination therapies using oncolytic virus and immunomodulation" (patent 11,065,285); and is supported by research grants from Celu larity, Codiak BioSciences, and AbbVie. She additionally has active granted patents for "miRNA for treating cancer and for use with adoptive immunotherapies" (patent 9,675,633) and "Concurrent chemotherapy and immuno therapy" (patent 9,399,662), with a patent pending for "Low intensity ultrasound combination cancer therapies" (international applications PCT/US2022/019435 and US 63/158,642).

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Section: R E I E W S E R I E S : I M M U N E E N V I R O N M E N T I ...supporting

confidence: 61%

Immune checkpoint blockade in glioblastoma: from tumor heterogeneity to personalized treatment

Arrieta¹,

Dmello²,

McGrail³

et al. 2023

Journal of Clinical Investigation

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“…Pathogenic POLE variations represent a unique subset of MSS and high-TMB tumors, often harboring very high TMB and responding well to ICI therapy. 27 , 28 …”

Section: Discussionmentioning

confidence: 99%

Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy in Patients With Metastatic Colorectal Cancer With Measures of Microsatellite Instability, Mismatch Repair, or Tumor Mutational Burden

Quintanilha¹,

Graf²,

Fisher³

et al. 2023

JAMA Netw Open

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ImportanceThe KEYNOTE-177 trial demonstrated that patients with metastatic colorectal cancer (MCRC) with high microsatellite instability (MSI-H) and/or mismatch repair deficiency (DMMR) have better outcomes when receiving first-line immune checkpoint inhibitors (ICIs) compared with chemotherapy. Data on performance of ICIs in patients with MCRC in standard practice settings remain limited, and direct MMR vs MSI outcome association comparisons are lacking.ObjectiveTo validate MSI (determined by next-generation sequencing [NGS]) as a biomarker of ICI effectiveness among patients with MCRC in standard practice settings and examine the association of MSI assessed by NGS, DMMR by immunohistochemistry, and tumor mutational burden (cutoff, 10 mutations/megabase) with ICI outcomes.Design, Setting, and ParticipantsThis comparative effectiveness research study of outcomes in prospectively defined biomarker subgroups used data from a deidentified clinicogenomic database and included patients who received Foundation Medicine testing (FoundationOne or FoundationOne CDx) during routine clinical care at approximately 280 US academic or community-based cancer clinics between March 2014 and December 2021. The population included 1 cohort of patients with MSI-H MCRC who received first-line ICIs or chemotherapy and a second cohort who received ICIs in any line of therapy (LOT) for biomarker examination.ExposuresICI therapy or chemotherapy assigned at physician discretion without randomization.Main Outcomes and MeasuresThe main outcomes were time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS). Hazard ratios were adjusted for known prognostic imbalances. Comparisons of explanatory power used the likelihood ratio test.ResultsA total of 138 patients (median age, 67.0 years [IQR, 56.2-74.0 years]; 73 [52.9%] female) with MSI-H MCRC received first-line ICIs or chemotherapy. A total of 182 patients (median age, 64.5 years [IQR, 55.2-72.0]; 98 [53.8%] female) received ICIs in any LOT. Patients receiving first-line ICIs vs chemotherapy had longer TTNT (median, not reached [NR] vs 7.23 months [IQR, 6.21-9.72 months]; adjusted hazard ratio [AHR], 0.17; 95% CI, 0.08-0.35; P &lt; .001), PFS (median, 24.87 months [IQR, 19.10 months to NR] vs 5.65 months [IQR, 4.70-8.34 months]; AHR, 0.31; 95% CI, 0.18-0.52; P &lt; .001), and OS (median, NR vs 24.1 months [IQR, 13.90 months to NR]; HR, 0.45; 95% CI, 0.23-0.88; P = .02). MSI added to DMMR better anticipated TTNT and PFS in patients receiving ICIs than DMMR alone. The same was not observed when DMMR evaluation was added to MSI.Conclusions and RelevanceIn this comparative effectiveness research study, MSI assessed by NGS robustly identified patients with favorable outcomes on first-line ICIs vs chemotherapy and appeared to better anticipate ICI outcomes compared with DMMR.

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“…This method is capable of correcting PCR errors, and identifying germline hypermutations by applying multilayer clustering algorithm [ 283 ]. Ma et al analyzed the impact of functional DNA damage repair (DDR) gene polymerase epsilon (POLE) mutations on tumor immune microenvironment post immune checkpoint blockade (ICB) therapy [ 284 ]. The authors observed upregulation of immune-related pathways in post-ICB Pole P286R tumors.…”

Section: In Silico Approaches Of Tme Profilingmentioning

confidence: 99%

“…The authors observed upregulation of immune-related pathways in post-ICB Pole P286R tumors. Evaluation of the TCR-beta CDR3 clonotypes isolated through MiXCR showed a higher rate of clonal expansion, richness and decreased evenness in post-ICB Pole P286R tumors [ 284 ]. Another method GLIPH, clusters TCRs based on their global similarity between CDR3 sequences, and the conserved motifs that provide common specificity to the receptors [ 285 ].…”

Section: In Silico Approaches Of Tme Profilingmentioning

confidence: 99%

Tumor microenvironment: barrier or opportunity towards effective cancer therapy

2022

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Tumor microenvironment (TME) is a specialized ecosystem of host components, designed by tumor cells for successful development and metastasis of tumor. With the advent of 3D culture and advanced bioinformatic methodologies, it is now possible to study TME’s individual components and their interplay at higher resolution. Deeper understanding of the immune cell’s diversity, stromal constituents, repertoire profiling, neoantigen prediction of TMEs has provided the opportunity to explore the spatial and temporal regulation of immune therapeutic interventions. The variation of TME composition among patients plays an important role in determining responders and non-responders towards cancer immunotherapy. Therefore, there could be a possibility of reprogramming of TME components to overcome the widely prevailing issue of immunotherapeutic resistance. The focus of the present review is to understand the complexity of TME and comprehending future perspective of its components as potential therapeutic targets. The later part of the review describes the sophisticated 3D models emerging as valuable means to study TME components and an extensive account of advanced bioinformatic tools to profile TME components and predict neoantigens. Overall, this review provides a comprehensive account of the current knowledge available to target TME.

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Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity

Cited by 39 publications

References 92 publications

Immune checkpoint blockade in glioblastoma: from tumor heterogeneity to personalized treatment

Immune checkpoint blockade in glioblastoma: from tumor heterogeneity to personalized treatment

Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy in Patients With Metastatic Colorectal Cancer With Measures of Microsatellite Instability, Mismatch Repair, or Tumor Mutational Burden

Tumor microenvironment: barrier or opportunity towards effective cancer therapy

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