Subclonal landscape of cancer drives resistance to immune therapy

Craig, Daniel J.; Bailey, Morgan M.; Noe, Olivia; Williams, Kada K.; Stanbery, Laura; Hamouda, Danae; Nemunaitis, John

doi:10.1016/j.ctarc.2021.100507

Cited by 10 publications

(7 citation statements)

References 81 publications

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Section: Discussionmentioning

confidence: 99%

“…45 46 Rather than being associated with neoantigen loads, bTMB might be more closely associated with tumor burden, 35 amount of ctDNA, 44 as well as with the increased intra-tumor heterogeneity especially induced by prior treatment. 47 Further, a recent meta-analysis revealed that the levels and the clearance of ctDNA can be used as independent prognostic factors for immunotherapy, while the prognostic impact of bTMB in cancer patients undergoing immunotherapy is worth further discussion and exploration. 48 However, for monitoring response to treatment with bTMB in patients with advanced NSCLC receiving ICIs, our results showed that the degree or percentage of change in bTMB was significantly associated with therapeutic effect of DCB/BOR, which indicated that changes in bTMB could possibly predict therapeutic response, even though there was no significant relationship between bTMB change and the long-term survival.…”

Section: Discussionmentioning

confidence: 99%

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Short-term dynamics of circulating tumor DNA predicting efficacy of sintilimab plus docetaxel in second-line treatment of advanced NSCLC: biomarker analysis from a single-arm, phase 2 trial

Han

Tang

Zhu

et al. 2022

J Immunother Cancer

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ObjectiveRobust biomarker predicting efficacy of immunotherapy is limited. Circulating tumor DNA (ctDNA) sought to effectively monitor therapeutic response as well as disease progression. This study aims to investigate predictive role of ctDNA short-term dynamic change (6 weeks postimmunotherapy) in a single-arm, phase 2 trial of sintilimab plus docetaxel for previously treated advanced non-small cell lung cancer (NSCLC) patients.MethodsA total of 33 patients with advanced NSCLC with disease progression during or after any first-line treatment were prospectively enrolled between 2019 and 2020. Patients received sintilimab (200 mg, day 1, every 3 weeks) plus docetaxel (75 mg/m2, day 3, every 3 weeks) for 4–6 cycles, followed by maintenance therapy with sintilimab (200 mg, day 1, every 3 weeks) until disease progression or unacceptable toxic effects. Blood samples were prospectively collected at baseline, and after 2 cycles of treatment (6 weeks post-treatment). All samples were subjected to targeted next-generation sequencing with a panel of 448 cancer-related genes. The landscape of high-frequency genomic profile of baseline and 6th week was described. Major molecular characteristics in preselected genes of interest associated with response to second-line chemoimmunotherapy were analyzed. The curative effects and prognosis of patients were evaluated.ResultsPatients with ctDNA clearance at 6th week had decreased tumor volume, while most patients with positive ctDNA at 6th-week experienced an increase in tumor volume. Positive 6th-week ctDNA was associated with significantly shorter progression-free survival (PFS) (91 vs NR days; p<0.0001) and overall survival (47 vs 467 days; p =0.0039). Clearance of clonal mutations and none new clonal formation at 6th week were associated with longer PFS (mPFS 89 vs 266 days, p =0.003). ctDNA clearance at 6th week was an independent risk factor for progression or death (HR=100 (95% CI 4.10 to 2503.00), p=0.005).ConclusionctDNA status and ctDNA mutation clearance putatively serve as predictive biomarkers for sintilimab combined with docetaxel chemotherapy in pretreated advanced NSCLC patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Short-term dynamics of circulating tumor DNA predicting efficacy of sintilimab plus docetaxel in second-line treatment of advanced NSCLC: biomarker analysis from a single-arm, phase 2 trial

Han

Tang

Zhu

et al. 2022

J Immunother Cancer

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“…Most of the XP-V skin tumors have, as expected, a high frequency of mutations. A high TMB is, per se , an emerging biomarker of sensitivity to immune checkpoint inhibitors, with accumulating evidence of more significant benefit of immunotherapy in tumors with high TMB 14,56 . Therefore, based on recent findings’ assumption that TMB is an important biomarker for a good outcome in cancer patients 57 , we strongly argue that immune checkpoint inhibitors might benefit to XP patients.…”

Section: Discussionmentioning

confidence: 99%

“…All basal cell carcinomas presented over 95% of SNVs (INDELs ~5%), while the average for the other two types of skin cancer, the squamous cell carcinoma and the melanoma, did not exceed 86% (INDELs ~14%) (Table 1). According to Foundation Medicine and FDA, the tumor mutation burden (TMB) is considered high when ten or more mutations per sequenced megabase are identified 14 . Ten of these tumors presented, accordingly, a high TMB.…”

Section: Xp-v Tumors' Samples Features and Single Base Substitution M...mentioning

confidence: 99%

Mutational signatures and increased retrotransposon insertions in Xeroderma Pigmentosum variant skin tumors

Corradi

Vilar

Buzatto

et al. 2022

Preprint

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Xeroderma Pigmentosum variant (XP-V) is an autosomal recessive disease with an increased risk to develop cutaneous neoplasms in sunlight exposed regions. These cells are deficient in the translesion synthesis DNA polymerase eta. Eleven skin tumors from a genetic cluster of XP-V patients had their exome sequenced. Mutational signatures identified for most tumors were related to ultraviolet exposure, such as C>T transitions targeted to pyrimidine dimers. However, four samples carry different mutational signatures, with C>A mutations associated with tobacco usage. Basal cell carcinomas showed a distinct C>A mutation spectra reflecting a novel mutational signature. Higher levels for retroposon insertions were detected in the XP-V tumors, compared to non-XP skin tumors. The results reveal other possible causes for XP-V tumors and the involvement of polymerase eta in suppressing retrotransposition. The expected high mutation burden, found in most of these tumors, renders these XP patients good candidates for immunotherapy with checkpoint blockers.

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“…However, from a genetic perspective, the accumulation of genomic mutations drives cancer initiation. Additionally, several studies have found significant differences in the TMB level and CNVs in non-small-cell carcinoma tumor samples with different ITH ( Zhao et al, 2019 ; Craig et al, 2022 ). Similarly, our analysis also showed that TMB and MATH scores were higher in the cluster 2 subtype than in the cluster 1 subtype.…”

Section: Discussionmentioning

confidence: 99%

Differential Infiltration of Immune Cells Driven by Tumor Heterogeneity Reveals Two Immune Subtypes in Lung Adenocarcinoma

et al. 2022

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Intra-tumoral heterogeneity (ITH) is a critical factor leading to aggressive progression and response to immunotherapy in lung adenocarcinoma (LUAD). However, the relationship between ITH and immune cells in the tumor microenvironment (TME) has not been systematically elucidated. In the present study, we evaluated the ITH status of LUAD samples based on the mutational data obtained from The Cancer Genome Atlas database. First, we identified five key immune pathways with a significantly continuous downtrend among normal, low-heterogeneous, and high-heterogeneous samples and further excavated nine key immune cells related to the key immune pathways and tumor heterogeneity. Then, two immune subtypes were defined by a consensus clustering algorithm based on the infiltration of these immune cells. Differences between these two immune subtypes were remarkable, including alterations of tumor mutation burden and DNA copy number variation at the genomic level, various metabolic pathways, and the different clinical outcome, which was also validated in two independent Gene Expression Omnibus datasets. The results revealed that ITH was significantly associated with prognosis and infiltrating immune cells in the TME. Our study provides novel insights in understanding the relationship between ITH and immune cells and contributes to the immunotherapy of LUAD patients.

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Subclonal landscape of cancer drives resistance to immune therapy

Cited by 10 publications

References 81 publications

Short-term dynamics of circulating tumor DNA predicting efficacy of sintilimab plus docetaxel in second-line treatment of advanced NSCLC: biomarker analysis from a single-arm, phase 2 trial

Short-term dynamics of circulating tumor DNA predicting efficacy of sintilimab plus docetaxel in second-line treatment of advanced NSCLC: biomarker analysis from a single-arm, phase 2 trial

Mutational signatures and increased retrotransposon insertions in Xeroderma Pigmentosum variant skin tumors

Differential Infiltration of Immune Cells Driven by Tumor Heterogeneity Reveals Two Immune Subtypes in Lung Adenocarcinoma

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