Germline Features Associated with Immune Infiltration in Solid Tumors

Shahamatdar, Sahar; He, Meng Xiao; Reyna, Matthew A.; Gusev, Alexander; AlDubayan, Saud H.; Allen, Eliezer M. Van; Ramachandran, Sohini

doi:10.1016/j.celrep.2020.02.039

Cited by 38 publications

(35 citation statements)

References 99 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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 cytokine-mediated 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 47-49 .…”

Section: Discussionmentioning

confidence: 99%

Prognostic value and peripheral immunologic correlates of early FDG PET response imaging in a phase II trial of risk-adaptive chemoradiation for unresectable non-small cell lung cancer

Bowen

Hippe

Hecking

et al. 2021

Preprint

View full text Add to dashboard Cite

Introduction: We hypothesized that FDG PET imaging during chemoradiation for unresectable non-small cell lung cancer (NSCLC) is prognostic for survival, and that tumor PET response is correlated with peripheral T-cell function. Methods: 45 patients with AJCCv7 stage IIB-IIIB NSCLC enrolled on the phase II FLARE-RT trial and received platinum-doublet chemotherapy concurrent with 6 weeks of radiation (NCT02773238). FDG PET imaging was performed prior to treatment start and after 24 Gy of radiation (week 3). PET response status was prospectively defined by multifactorial radiologic interpretation. PET responders received 60 Gy in 30 fractions, while non-responders received concomitant boosts to 74 Gy in 30 fractions. Peripheral blood was drawn synchronously with PET imaging, from which germline DNA sequencing, T-cell receptor (TCR) sequencing, and plasma cytokines analysis were performed. Results: Median follow-up was 18.8 months, 1-year overall survival (OS) 82%, 1-year progression-free survival (PFS) 53%, and 1-year locoregional control (LRC) 88%. Higher mid-treatment PET total lesion glycolysis was detrimental to OS (1-yr 87% vs. 63%, p<0.001), PFS (1-yr 60% vs. 26%, p=0.044) and LRC (1-yr 94% vs. 65%, p=0.012), even after adjustment for clinical/treatment factors. Higher PD-L1 tumor proportion score (TPS) was correlated with PET response (p=0.017): 6/6 patients with high PD-L1 (TPS>50%) were classified as PET responders, while 4/5 patients classified as PET non-responders had negative PD-L1 (TPS<1%). Higher TCR richness and clone distribution slope was associated with improved OS (p=0.018-0.035); clone distribution slope was correlated with PET response (p=0.031). Germline DNA alterations in immunologic pathways had an outsized effect on OS and PET response; of the top 30 SNPs ranked by association with PET response status (p<0.016), a plurality (13/30) came from immunologic pathways. Conclusions: Mid-chemoradiation PET imaging is prognostic for survival; PET response may be linked to tumor and peripheral T-cell biomarkers.

show abstract

Section: Discussionmentioning

confidence: 99%

Prognostic value and peripheral immunologic correlates of early FDG PET response imaging in a phase II trial of risk-adaptive chemoradiation for unresectable non-small cell lung cancer

Bowen

Hippe

Hecking

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…TME and TMB are two tumor characteristics important in immunotherapy response and prognosis. Recent studies have shown that germline variants can shape certain immune features within the TME of solid tumors [34][35][36] . Consistent with and complementary to these observations, our results show that the personal germline RDV load of a patient can impact their TME (see Supplementary Figure S4, Supplementary Table S11).…”

Section: Discussionmentioning

confidence: 99%

“…Next, in light of recent findings on the impact of germline variants on tumor immune microenvironment (TME) in various cancers [34][35][36] , we tested the association of increased germline RDV load in CPD, DDR, SCD and FA gene-sets with TME immune cell fractions. Briefly, to avoid any potential biases from B-cell immune signatures in blood cancers, we focused on 6,277 participants with solid tumors in TCGA by excluding 94 TCGA participants with hematological malignancies.…”

Section: Data-driven Analysis Of 17810 Gene-sets In Msigdb Again Identified Rdv Burden Inmentioning

confidence: 99%

Germline rare deleterious variant load alters cancer risk, age of onset and tumor characteristics

Onel

Gnjatic

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Inherited genetic variants play an important role in cancer susceptibility. Recent studies show that rare, deleterious variants (RDVs) in a few genes are critical determinants of heritable cancer risk. Better understanding of germline RDVs will contribute to improved precision prevention, screening and treatment. Methods: We have performed the largest to date jointly processed germline pan-cancer case-control association study from whole-exome sequencing (WES) data of 20,789 participants, split into discovery and validation cohorts. We focused on high-penetrance RDVs based on ClinVar database. To increase the statistical power, we pursued a collapsing approach and compared the cumulative RDV burden at gene and gene-set levels using penalized logistic regression. Next, we investigated how the accumulation of RDVs in an individual (RDV load) is associated with cancer risk. Finally, we studied how personal RDV load in specific gene-sets affected i) age of diagnosis; ii) tumor immune microenvironment; and iii) tumor mutational burden using Mann-Whitney U test and Kruskal-Wallis test. Results: Our results confirm known associations between cancer risk and germline RDVs in BRCA1/2 genes, and show associations with risk for RDVs in Fanconi Anemia (FA), DNA damage repair (DDR), cancer predisposition (CPD) and somatic cancer driver gene-sets in two independent cohorts. Furthermore, increased personal germline RDV load in these gene-sets increased cancer risk, and once cancer developed, tumor characteristics. Notably, we show that the personal RDV load of an individual in FA, DDR or CPD genes is a potential marker for younger age of onset, M1 macrophage fraction in tumor microenvironment, and, in specific cancers, increased tumor mutation burden. Conclusions: Our findings will help better stratification of individuals at high cancer risk, as well as the characterization of the influence of their personal germline RDV load on age of diagnosis, tumor microenvironment and mutational burden. These high-risk individuals may benefit from increased surveillance, earlier screening and prevention efforts, and treatments that exploit their tumor characteristics, improving prognosis.

show abstract

“…The copyright holder for this preprint (which this version posted April 15, 2021. ; https://doi.org/10.1101/2021.04.14.436660 doi: bioRxiv preprint immune infiltration levels and immune pathways, such as TGF-β and IFN-ɣ 9,10,23 . eGenes (genes with significant cis-eQTLs) in the TCGA are enriched for immune-related genes and associated with immune cell abundance within the tumor immune microenvironment (TIME) 24 .…”

Section: Efforts To Identify Germline Variation Influencing Anti-tumor Immune Responses Have Pointed To Effects Onmentioning

confidence: 99%

“…Germline variation is responsible for a considerable proportion of variation in immune traits in healthy populations 7,8 . In the context of tumors, germline variants have the potential to influence immune infiltration, antigen presentation and immunotherapy responses 9,10 . Autoimmune germline variants modify ICB response and variants underlying leukocyte genes predict tumor recurrence in breast cancer patients 11,12 .…”

Section: Introductionmentioning

confidence: 99%

Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response

Pagadala

Vh²,

Pérez-Guijarro

et al. 2021

Preprint

View full text Add to dashboard Cite

With the continued promise of immunotherapy as an avenue for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer risk screening and treatment strategies. Using genotypes from over 8,000 European individuals in The Cancer Genome Atlas (TCGA) and 137 heritable tumor immune phenotype components (IP components), we identified and investigated 482 TIME associations and 475 unique TIME-associated variants. Many TIME-associated variants influence gene activities in specific immune cell subsets, such as macrophages and dendritic cells, and interact to promote more extreme TIME phenotypes. TIME-associated variants were predictive of immunotherapy response in human cohorts treated with immune-checkpoint blockade (ICB) in 3 cancer types, causally implicating specific immune-related genes that modulate myeloid cells of the TIME. Moreover, we validated the function of these genes in driving tumor response to ICB in preclinical studies. Through an integrative approach, we link host genetics to TIME characteristics, informing novel biomarkers for cancer risk and target identification in immunotherapy.

show abstract

Germline Features Associated with Immune Infiltration in Solid Tumors

Cited by 38 publications

References 99 publications

Prognostic value and peripheral immunologic correlates of early FDG PET response imaging in a phase II trial of risk-adaptive chemoradiation for unresectable non-small cell lung cancer

Prognostic value and peripheral immunologic correlates of early FDG PET response imaging in a phase II trial of risk-adaptive chemoradiation for unresectable non-small cell lung cancer

Germline rare deleterious variant load alters cancer risk, age of onset and tumor characteristics

Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response

Contact Info

Product

Resources

About