Germline features associated with immune infiltration in solid tumors

Abstract

24Given the clinical success of immune checkpoint blockade (ICB) across a diverse set of solid 25 tumors, and the emerging role for different immune infiltrates in contributing to response to ICB, 26 a comprehensive assessment of the properties that dictate immune infiltrations may reveal new 27 biological insights and inform the development of new effective therapies. Multiple studies have 28 examined somatic and functional immune properties associated with different tumor infiltrates; 29 however, germline features that associate with specific immune infiltrates in cancers have been 30 incompletely characterized. Here, we analyzed over 7 million autosomal germline variants in 31 the TCGA cohort (5788 European-ancestry samples across 30 cancer types) and tested for pan-32 cancer association with established immune-related phenotypes that describe the tumor immune 33 microenvironment. We identified: one SNP associated with the fraction of follicular helper T 34 cells in bulk tumor; 77 unique candidate genes, some of which are involved in cytokine-mediated 35 signaling (e.g. CNTF and TRIM34 ) and cancer pathogenesis (e.g. ATR and AKAP9 ); and 36 subnetworks with genes that are part of DNA repair (RAD51 and XPC ) and transcription 37 2 elongation (CCNT2 ) pathways. We found a positive association between polygenic risk for 38 rheumatoid arthritis and absolute fraction of infiltrating CD8 T cells. Overall, we identified 39 multiple germline genetic features associated with specific tumor-immune phenotypes across 40 cancer, and developed a framework for probing inherited features that contribute to variation 41 in immune infiltration.42

A proteogenomic portrait of lung squamous cell carcinoma

“…(E) Overlap between differentially regulated mRNA and proteins between Hot versus Cold and Warm versus Cold tumors, and eGenes downstream of cis-eQTLs and cis-pQTLs. Recent studies have suggested the importance of germline variants in the immune profiles of solid tumors (Lim et al, 2018;Shahamatdar et al, 2020;Tian et al, 2021). Among 319 cis-pQTLs (cis-regulating the cognate protein) identified in this study, only 38 were also cis-eQTLs (cis-regulating cognate RNA)(Table S6).…”

Increased Expression Together with the Gene Regulation Network of NEIL3 Predicts Poor Prognosis and Correlates with Immune Infiltrates in Hepatocellular Carcinoma

“…Tregs, and exhausted T cells. These gene markers had been reported in previous studies [22][23][24][25][26].…”

Prognostic Value of Early Fluorodeoxyglucose-Positron Emission Tomography Response Imaging and Peripheral Immunologic Biomarkers: Substudy of a Phase II Trial of Risk-Adaptive Chemoradiation for Unresectable Non-Small Cell Lung Cancer

“…The JAK-STAT signaling pathway plays critical roles in cytokine receptors and can modulate the polarization of T helper cells. A recent report by Shahamatdar et al 46 analyzing germline variants in the TCGA cohort demonstrated that host genetics are associated with phenotypes that describe the immune component of the tumor microenvironment; they found one SNP associated with the amount of infiltrating follicular helper T cells; and 23 candidate genes, some of which are involved in cytokinemediated signaling. Our patient cohort supports prior findings that patients with greater TCR richness in the peripheral blood had improved survival compared with patients with less clonal richness [47][48][49] .…”