PBRM1 Inactivation Promotes Upregulation of Human Endogenous Retroviruses in a HIF-Dependent Manner

Zhou, Mi; Leung, Janny; Gessner, Kathryn H.; Hepperla, Austin J.; Simon, Jeremy M.; Davis, Ian J.; Kim, William Y.

doi:10.1158/2326-6066.cir-21-0480

Cited by 15 publications

(9 citation statements)

References 34 publications

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“…Notably, PBRM1 mutations, which lead to further HIF upregulation [55] and angiogenic expression [56, 57], were also positively associated with HERV (Fig. S7b), consistent with a recent report [58]. In agreement with [54] we then confirmed the association between the median expression of different HERV loci and TIL abundance (Fig.…”

Section: Resultssupporting

confidence: 91%

Spatiotemporal evolution of the ccRCC microenvironment links intra-tumoral heterogeneity to immune escape

Golkaram

Kuo

Gupta

et al. 2022

Preprint

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Background Intratumoral heterogeneity (ITH) is a hallmark of clear cell renal cell carcinoma (ccRCC) that reflects the trajectory of evolution and influences clinical prognosis. Here we seek to elucidate how ITH and tumor evolution during immune checkpoint inhibitor (ICI) treatment can lead to therapy resistance. Methods Here, we spatiotemporally profiled the genomic and immunophenotypic characteristics of 29 ccRCC patients, including pre- and post-therapy samples from 17 ICI treated patients. Deep multi-regional whole exome and transcriptome sequencing were performed on 29 patients at different time points before and after ICI therapy. T cell repertoire was also monitored from tissue and peripheral blood collected from a subset of patients to study T cell clonal expansion during ICI therapy. Results Angiogenesis, lymphocytic infiltration, and myeloid infiltration varied significantly across regions of the same patient, potentially confounding their utility as biomarkers of ICI response. Elevated ITH associated with a constellation of both genomic features (HLA LOH, CDKN2A/B loss) and microenvironmental features, including elevated myeloid expression, reduced peripheral T cell receptor (TCR) diversity, and putative neoantigen depletion. Hypothesizing that ITH may itself play a role in shaping ICI response, we derived a transcriptomic signature associated with neoantigen depletion that strongly associated with response to ICI and targeted therapy treatment in several independent clinical trial cohorts. Conclusions These results argue that genetic and immune heterogeneity jointly co-evolve and influence response to ICI in ccRCC. Trial registration We completed a single-arm pilot study at Memorial Sloan Kettering Cancer Center (MSKCC; ClinicalTrials.gov identifier NCT02595918) to examine the safety and feasibility of neoadjuvant nivolumab in patients with localized RCC.

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Section: Resultssupporting

confidence: 91%

Spatiotemporal evolution of the ccRCC microenvironment links intra-tumoral heterogeneity to immune escape

Golkaram

Kuo

Gupta

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Notably, PBRM1 mutations, which lead to further HIF upregulation [54] and angiogenic expression [55,56], were also positively associated with HERV (Additional file 2: Fig. S8B), consistent with a recent report [57]. In agreement with [53], we then confirmed the association between the median expression of different HERV loci and TIL abundance (Additional file 2: Fig.…”

Section: Ici Therapy Is Associated With Loss Of Putative Neoantigens ...supporting

confidence: 89%

Spatiotemporal evolution of the clear cell renal cell carcinoma microenvironment links intra-tumoral heterogeneity to immune escape

et al. 2022

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Background Intratumoral heterogeneity (ITH) is a hallmark of clear cell renal cell carcinoma (ccRCC) that reflects the trajectory of evolution and influences clinical prognosis. Here, we seek to elucidate how ITH and tumor evolution during immune checkpoint inhibitor (ICI) treatment can lead to therapy resistance. Methods Here, we completed a single-arm pilot study to examine the safety and feasibility of neoadjuvant nivolumab in patients with localized RCC. Primary endpoints were safety and feasibility of neoadjuvant nivolumab. Then, we spatiotemporally profiled the genomic and immunophenotypic characteristics of 29 ccRCC patients, including pre- and post-therapy samples from 17 ICI-treated patients. Deep multi-regional whole-exome and transcriptome sequencing were performed on 29 patients at different time points before and after ICI therapy. T cell repertoire was also monitored from tissue and peripheral blood collected from a subset of patients to study T cell clonal expansion during ICI therapy. Results Angiogenesis, lymphocytic infiltration, and myeloid infiltration varied significantly across regions of the same patient, potentially confounding their utility as biomarkers of ICI response. Elevated ITH associated with a constellation of both genomic features (HLA LOH, CDKN2A/B loss) and microenvironmental features, including elevated myeloid expression, reduced peripheral T cell receptor (TCR) diversity, and putative neoantigen depletion. Hypothesizing that ITH may itself play a role in shaping ICI response, we derived a transcriptomic signature associated with neoantigen depletion that strongly associated with response to ICI and targeted therapy treatment in several independent clinical trial cohorts. Conclusions These results argue that genetic and immune heterogeneity jointly co-evolve and influence response to ICI in ccRCC. Our findings have implications for future biomarker development for ICI response across ccRCC and other solid tumors and highlight important features of tumor evolution under ICI treatment. Trial registration The study was registered on ClinicalTrial.gov (NCT02595918) on November 4, 2015.

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“…Efforts have been made to search for predictors of ICI response in ccRCC patients, and several molecules are shown to be useful in some reports but fail to be validated by others ( 22 – 27 , 42 , 43 ). Intriguingly, the presence of high CD8 T cells in tumors is associated with poor prognosis ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

The cuproptosis-associated 13 gene signature as a robust predictor for outcome and response to immune- and targeted-therapies in clear cell renal cell carcinoma

et al. 2022

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Cuproptosis, the newly identified form of regulatory cell death (RCD), results from mitochondrial proteotoxic stress mediated by copper and FDX1. Little is known about significances of cuproptosis in oncogenesis. Here we determined clinical implications of cuproptosis in clear cell renal cell carcinoma (ccRCC). Based on the correlation and survival analyses of cuproptosis-correlated genes in TCGA ccRCC cohort, we constructed a cuproptosis-associated 13 gene signature (CuAGS-13) score system. In both TCGA training and two validation cohorts, when patients were categorized into high- and low-risk groups according to a median score as the cutoff, the CuAGS-13 high-risk group was significantly associated with shorter overall survival (OS) and/or progression-free survival (PFS) independently (P<0.001 for all). The CuAGS-13 score assessment could also predict recurrence and recurrence-free survival of patients at stage I – III with a high accuracy, which outperformed the ccAccB/ClearCode34 model, a well-established molecular predictor for ccRCC prognosis. Moreover, patients treated with immune checkpoint inhibitors (ICIs) acquired complete/partial remissions up to 3-time higher coupled with significantly longer PFS in the CuAGS-13 low- than high-risk groups in both training and validation cohorts of ccRCCs (7.2 – 14.1 vs. 2.1 – 3.0 months, P<0.001). The combination of ICI with anti-angiogenic agent Bevacizumab doubled remission rates in CuAGS-13 high-risk patients while did not improve the efficacy in the low-risk group. Further analyses showed a positive correlation between CuAGS-13 and TIDE scores. We also observed that the CuAGS-13 score assessment accurately predicted patient response to Sunitinib, and higher remission rates in the low-risk group led to longer PFS (Low- vs. high-risk, 13.9 vs. 5.8 months, P = 5.0e-12). Taken together, the CuAGS-13 score assessment serves as a robust predictor for survival, recurrence, and response to ICIs, ICI plus anti-angiogenic drugs and Sunitinib in ccRCC patients, which significantly improves patient stratifications for precision medicine of ccRCC.

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PBRM1 Inactivation Promotes Upregulation of Human Endogenous Retroviruses in a HIF-Dependent Manner

Cited by 15 publications

References 34 publications

Spatiotemporal evolution of the ccRCC microenvironment links intra-tumoral heterogeneity to immune escape

Spatiotemporal evolution of the ccRCC microenvironment links intra-tumoral heterogeneity to immune escape

Spatiotemporal evolution of the clear cell renal cell carcinoma microenvironment links intra-tumoral heterogeneity to immune escape

The cuproptosis-associated 13 gene signature as a robust predictor for outcome and response to immune- and targeted-therapies in clear cell renal cell carcinoma

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