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Mutation Drivers of Immunological Responses to Cancer.

ABSTRACT: In cancer immunology, somatic missense mutations have been mostly studied with regard to their role in the generation of neoantigens. However, growing evidence suggests that mutations in certain genes, such as CASP8 or TP53, influence the immune response against a tumor by other mechanisms. Identifying these genes and mechanisms is important because, just as the identification of cancer driver genes led to the development of personalized cancer therapies, a comprehensive catalog of such cancer immunity drivers will aid in the development of therapies aimed at restoring antitumor immunity. Here, we present an algorithm, domainXplorer, that can be used to identify potential cancer immunity drivers. To demonstrate its potential, we used it to analyze a dataset of 5,164 tumor samples from The Cancer Genome Atlas (TCGA) and to identify protein domains in which mutation status correlates with the presence of immune cells in cancer tissue (immune infiltrate). We identified 122 such protein regions, including several that belong to proteins with known roles in immune response, such as C2, CD163L1, or FC?R2A. In several cases, we show that mutations within the same protein can be associated with more or less immune cell infiltration, depending on the specific domain mutated. These results expand the catalog of potential cancer immunity drivers and highlight the importance of taking into account the structural context of somatic mutations when analyzing their potential association with immune phenotypes. Cancer Immunol Res; 4(9); 789-98. ©2016 AACR.

SUBMITTER: Porta-Pardo E

PROVIDER: S-EPMC5886853 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Mutation Drivers of Immunological Responses to Cancer.

Porta-Pardo Eduard E Godzik Adam A

Cancer immunology research 20160711 9

In cancer immunology, somatic missense mutations have been mostly studied with regard to their role in the generation of neoantigens. However, growing evidence suggests that mutations in certain genes, such as CASP8 or TP53, influence the immune response against a tumor by other mechanisms. Identifying these genes and mechanisms is important because, just as the identification of cancer driver genes led to the development of personalized cancer therapies, a comprehensive catalog of such cancer i ...[more]

PMID: 27401919

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Project description:Neural stem cell (NSC) therapy is a promising therapeutic strategy for stroke. Researchers have frequently carried out genetic modification or gene editing of stem cells to improve survival or therapeutic function. However, NSC transplantation carries the risk of immune rejection, and genetic modification or gene-editing might further increase this risk. For instance, recent studies have reported on manipulating the stem cell genome and transplantation via the insertion of an exogenous gene derived from magnetotactic bacteria. However, whether transgene-modified stem cells are capable of inducing immunological reactions has not been explored. Although NSCs rarely express the major histocompatibility complex (MHC), they can still cause some immunological issues. To investigate whether transgene-modified NSCs aggravate immunological responses, we detected the changes in peripheral immune organs and intracerebral astrocytes, glial cells, and MHC-I and MHC-II molecules after the injection of GFP-labeled or mms6-GFP-labeled NSCs in a rat model. Xenogeneic human embryonic kidney (HEK-293T) cells were grafted as a positive control group. Our results indicated that xenogeneic cell transplantation resulted in a strong peripheral splenic response, increased astrocytes, enhanced microglial responses, and upregulation of MHC-I and MHC-II expression on the third day of transplantation. But they decreased obviously except Iba-1 positive cells and MHC-II expression. When injection of both mms6-GFP-labeled NSCs and GFP-labeled NSCs also induced similar responses as HEK-293T cells on the third days, but MHC-I and MHC-II expression decreased 3 weeks after transplantation. In addition, mms6 transgene-modified NSCs did not produce peripheral splenic response responses as well as astrocytes, microglial cells, MHC-I and MHC-II positive cells responses when compared with non-modified NSCs. The present study provides preliminary evidence that transgenic modification does not aggravate immunological responses in NSC transplantation.

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Mutation Drivers of Immunological Responses to Cancer.

Publications

Mutation Drivers of Immunological Responses to Cancer.

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