Autoimmune genetic risk variants as germline biomarkers of response to melanoma immune-checkpoint inhibition

Chat, Vylyny; Ferguson, Robert; Simpson, Danny; Kazlow, Esther; Lax, Rebecca; Moran, Una; Pavlick, Anna C.; Frederick, Dennie T.; Boland, Genevieve M.; Sullivan, Ryan J.; Ribas, Antoni; Flaherty, Keith T.; Osman, Iman; Weber, Jeffrey S.; Kirchhoff, Tomas

doi:10.1007/s00262-019-02318-8

Cited by 47 publications

(46 citation statements)

References 42 publications

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“…were associated with increased risk of T1DM and vitiligo and were associated with increased IFN signaling signature in our dataset, suggesting a positive correlation between genetic risk for T1DM, vitiligo, and interferon signature in tumor. Since interferon signatures have been associated with a positive prognosis for patients on immunotherapy (Ayers et al, 2017), our results suggest that this SNP may also be associated with efficacy among patients receiving immunotherapy, which is consistent with preliminary data in melanoma patients receiving checkpoint inhibitors (Chat et al, 2019). In contrast, the A allele of rs2111485 and C allele of rs1190760 are associated with decreased risk of psoriasis and inflammatory bowel disease Tsoi et al, 2012).…”

Section: Tcga Only Includes Common Variant Germline Data and Not Wholsupporting

confidence: 87%

Germline genetic contribution to the immune landscape of cancer

Sayaman

Saad

Thórsson

et al. 2020

Preprint

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SummaryThe role of germline genetics in shaping the tumor immune landscape is largely unknown. Using genotypes from >9,000 individuals in The Cancer Genome Atlas, we investigated the association of common and rare variants with 139 well-defined immune traits. Our analysis of common variants identified 10 immune traits with significant heritability estimates, and an additional 23 with suggestive heritability, including estimates of T-cell subset abundance and interferon signaling. We performed genome-wide association on the 33 heritable traits and identified 23 genome-wide significant loci associated with at least one immune trait, including SNPs in the IFIH1 locus previously associated with several autoimmune diseases. We also found significant associations between immune traits and pathogenic or likely-pathogenic rare variants in BRCA1 and in genes functionally linked to telomere stabilization, and Wnt/Beta-catenin signaling. We conclude that germline genetic variants significantly impact the composition and functional orientation of the tumor immune microenvironment.

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Section: Tcga Only Includes Common Variant Germline Data and Not Wholsupporting

confidence: 87%

Germline genetic contribution to the immune landscape of cancer

Sayaman

Saad

Thórsson

et al. 2020

Preprint

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“…And safety of anti-PD-1/PD-L1 targeted therapies was significantly associated with gene SNPs including UNG, IFNW1, CTLA4, PD-L1, and IFNL4 genes (130). Besides that, rs17388568, which maps to a locus of IL2 gene and IL21 gene, was correlated with a higher response to anti-PD-1 targeting therapy (131). CD8, PD-1, and PD-L1 expression in the tumor and at the invasive margin significantly correlated with treatment outcome (P = 0.001) (132).…”

Section: The Current Potential Biomarkers Used To Evaluate the Feasibmentioning

confidence: 92%

Clinical and Recent Patents Applications of PD-1/PD-L1 Targeting Immunotherapy in Cancer Treatment—Current Progress, Strategy, and Future Perspective

Guo¹,

Wei²,

Lin

et al. 2020

Front. Immunol.

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Targeting PD-L1 and PD-1 interactions is a relatively new therapeutic strategy used to treat cancer. Inhibitors of PD-1/PD-L1 include peptides, small molecule chemical compounds, and antibodies. Several approved antibodies targeting PD-1 or PD-L1 have been patented with good curative effect in various cancer types in clinical practices. While the current antibody therapy is facing development bottleneck, some companies have tried to develop PD-L1 companion tests to select patients with better diagnosis potential. Meanwhile, many companies have recently synthesized small molecule inhibitors of PD-1/PD-L1 interactions and focused on searching for novel biomarker to predict the efficacy of anti-PD-1/PD-L1 drugs. This review summarized clinical studies and patent applications related to PD-1/PD-L1 targeted therapy and also discussed progress in inhibitors of PD-1/PD-L1.

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“…Beyond tumor-cell-intrinsic oncogenic events that affect immunotherapy resistance, additional host factors have been identified that contribute to the degree of endogenous T cell infiltration in patients. These include the composition of the commensal microbiota 11 and germline polymorphisms in immunoregulatory genes 12 . The probability of clinical response to immunotherapy approaches such as anti-PD-1 may ultimately depend on the integration of the functional effects of multiple biological processes.…”

Section: Thomas F Gajewski and Jessica Fesslermentioning

confidence: 99%