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Germline Genetic Variants May Influence Tumor Immune Microenvironment, Treatment Response

This article has been updated to include additional comment from a study author.

NEW YORK – Germline genetic variants can influence the tumor immune microenvironment and, potentially, immunotherapy response, a new study has found.

Immunotherapy is increasingly used to treat solid tumors, but fewer than 15 percent of patients respond to it. Part of what influences response, scientists have recently found, is what immune cells have infiltrated the tumors, which could itself be governed by host genetics.

An international team of researchers examined the effects of common and rare germline variations on immune traits in about 9,000 cancer patients from The Cancer Genome Atlas. As they reported in the journal Immunity on Tuesday, researchers led by Sidra Medicine's Davide Bedognetti and the University of California, San Francisco's Elad Ziv found that germline alterations affect immune infiltration of tumors or immune cell abundance and that certain variants may be immune modulators. 

The findings suggested to Bedognetti that "that responsiveness to immunotherapy might be influenced by the genes we are born with, and that different approaches are needed in different patients," as he noted in an email.

In an approach that combined heritability analyses, genome-wide association studies, and rare variant analyses of 30 solid cancers from TCGA, the researchers homed in on genetic variants that influence immune traits among cancer patients. They examined a total of 139 immune traits that fit broadly into six subtypes that influence, for instance, the proportion of immune cells overall, the portion of leukocytes, and the expression of certain immune-related markers.

The researchers' heritability analyses estimated that up to 20 percent of the variance in some immune traits could be explained by common genetic variants. They further found that about a quarter of the immune traits they analyzed were heritable. For instance, they estimated that the abundance of cytotoxic T, NK, and Tfh cells are strongly influenced by germline genetics, a heritability of about 20 percent.

From this, the researchers chose 33 immune traits with nominally significant heritability to undergo analysis in genome-wide association studies drawing on 9,603 individuals. For 10 of these immune traits, they uncovered nearly 600 genome-wide significant associations at 23 loci. 

Most of these loci were linked to leukocyte subset enrichment and IFN signaling, which is typically activated in viral response and in some auto-immune disorders. 

The researchers homed in on two significant loci for IFN-ɣ signatures, in particular one that included two SNPs within the IFIH1 gene. That gene has previously been linked to a number of autoimmune disorders, indicating a link between autoimmunity and immune repose. The researchers further noted that, as IFN signatures have been tied to immunotherapy response, these SNPs could be associated with immunotherapy efficacy.

Meanwhile, they additionally found a number of IFN-linked SNPs near TMEM108. Though  TMEM108 does not appear to affect IFN signaling, it might act through the Wnt-β-catenin pathway, the researchers noted. They further identified 14 genomic loci associated with immune traits that are part of the T cell/cytotoxic module, including ones implicating RBL1, which is involved in DNA repair.

At the same time, the researchers examined the influence of rare variants on immune traits to find they too may influence the immune environment. BRCA1 mutations and alterations affecting the Wnt-β-catenin and telomere-stabilization pathway, for instance, may act as immune modulators.

The findings suggested to the researchers that both common and rare germline variants shape the tumor microenvironment. According to Bedognetti, future studies could investigate whether an "immunogenetic score" might be able to stratify patients based on their predicted response to immunotherapy.

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