Dark genome, bright ideas: Recent approaches to harness transposable elements in immunotherapies
2022; Cell Press; Volume: 40; Issue: 8 Linguagem: Inglês
10.1016/j.ccell.2022.07.003
ISSN1878-3686
AutoresAshley Reid Cahn, Nina Bhardwaj, Nicolas Vabret,
Tópico(s)Advanced biosensing and bioanalysis techniques
ResumoTransposable elements (TEs), which make up almost half of the human genome, often display altered expression in cancers. Here, we review recent progress in elucidating the role of TEs as mediators of immune responses in cancer and discuss how novel therapeutic strategies can harness TE immunogenicity for cancer immunotherapy. Transposable elements (TEs), which make up almost half of the human genome, often display altered expression in cancers. Here, we review recent progress in elucidating the role of TEs as mediators of immune responses in cancer and discuss how novel therapeutic strategies can harness TE immunogenicity for cancer immunotherapy. Transposable elements (TEs) are current or previous mobile elements within the genome. In humans, they constitute 46% of the genome and are classified into two main types: DNA transposons and retroelements. Retroelements are further divided into three broad subclasses: long interspersed nuclear elements (LINEs), short interspersed nuclear elements (SINEs), and long terminal repeat (LTR)/endogenous retrovirus (ERV) elements (Figure 1A). A growing body of research has now established that TE-derived nucleic acids are ligands of innate immune sensors in the tumor microenvironment (TME). Specifically, the remodeling of the epigenetic landscape concomitant with cancer cell transformation can lead to reactivation of TEs, which have the potential to activate nucleic acid-sensing pathways. These pathways include sensing of RNA through RIG-I-like receptors (RLRs) and Toll-like receptor 3 (TLR3) and sensing of reverse-transcribed complementary DNA (cDNA) through cyclic GMP-AMP synthase (cGAS). Two RLRs, RIG-I and MDA5, are primarily responsible for sensing immunogenic intracellular RNA. Upon activation, they interact with mitochondrial antiviral signaling (MAVS) protein and induce IRF3, IRF7, and NF-κB translocation to the nucleus, leading to the induction of type I interferon (IFN-I) and pro-inflammatory cytokines. RIG-I is preferentially activated by short double-stranded RNA (dsRNA) with 5′-triphosphate moieties, while MDA5 primarily binds longer dsRNAs. Importantly, several classes of TEs can harbor these structural features typically found in viruses. Experimental approaches such as dsRNA antibody capture or dsRNA enrichment through single-stranded-specific RNase treatment showed that several classes of TEs expressed in cancer cell lines—including families of ERV, LINEs, or SINEs—can lead to the formation of dsRNA (Sheng et al., 2018Sheng W. LaFleur M.W. Nguyen T.H. Chen S. Chakravarthy A. Conway J.R. Li Y. Chen H. Yang H. Hsu P.H. et al.LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade.Cell. 2018; 174: 549-563.e19https://doi.org/10.1016/j.cell.2018.05.052Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar; Tunbak et al., 2020Tunbak H. Enriquez-Gasca R. Tie C.H.C. Gould P.A. Mlcochova P. Gupta R.K. Fernandes L. Holt J. van der Veen A.G. Giampazolias E. et al.The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s.Nat. Commun. 2020; 11: 5387https://doi.org/10.1038/s41467-020-19170-5Crossref PubMed Scopus (31) Google Scholar; Choi et al., 2021Choi H. Kwon J. Cho M.S. Sun Y. Zheng X. Wang J. Bouker K.B. Casey J.L. Atkins M.B. Toretsky J. Han C. Targeting DDX3X triggers antitumor immunity via a dsrna-mediated tumor-intrinsic type I interferon response.Cancer Res. 2021; 81: 3607-3620https://doi.org/10.1158/0008-5472.can-20-3790Crossref PubMed Google Scholar). While the role of MDA5 in sensing these dsRNA populations had been previously demonstrated through genetic depletion of this sensor, inverted repeats (IR)-Alu (a family of SINEs) was identified as the primary source of TE-derived dsRNA binding MDA5 in patient-derived colorectal cancer cells (Mehdipour et al., 2020Mehdipour P. Marhon S.A. Ettayebi I. Chakravarthy A. Hosseini A. Wang Y. de Castro F.A. Loo Yau H. Ishak C. Abelson S. et al.Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency.Nature. 2020; 588: 169-173https://doi.org/10.1038/s41586-020-2844-1Crossref PubMed Scopus (63) Google Scholar). IR-Alu, likely forming stem-loops from unidirectionally transcribed repeats, made up to 53% of MDA5-bound RNA at baseline and 73% after treatment with decitabine, an inhibitor of DNA methyltransferase (DNMT) that suppresses IR-Alu expression by DNA methylation (Mehdipour et al., 2020Mehdipour P. Marhon S.A. Ettayebi I. Chakravarthy A. Hosseini A. Wang Y. de Castro F.A. Loo Yau H. Ishak C. Abelson S. et al.Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency.Nature. 2020; 588: 169-173https://doi.org/10.1038/s41586-020-2844-1Crossref PubMed Scopus (63) Google Scholar). Investigation of RIG-I as a sensor of TE expression has been more limited than MDA5, and reports have been conflicting, with some studies demonstrating an absence or little impact on interferon stimulated genes (ISGs) activation following RIG-I downregulation (Sheng et al., 2018Sheng W. LaFleur M.W. Nguyen T.H. Chen S. Chakravarthy A. Conway J.R. Li Y. Chen H. Yang H. Hsu P.H. et al.LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade.Cell. 2018; 174: 549-563.e19https://doi.org/10.1016/j.cell.2018.05.052Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar; Tunbak et al., 2020Tunbak H. Enriquez-Gasca R. Tie C.H.C. Gould P.A. Mlcochova P. Gupta R.K. Fernandes L. Holt J. van der Veen A.G. Giampazolias E. et al.The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s.Nat. Commun. 2020; 11: 5387https://doi.org/10.1038/s41467-020-19170-5Crossref PubMed Scopus (31) Google Scholar; Choi et al., 2021Choi H. Kwon J. Cho M.S. Sun Y. Zheng X. Wang J. Bouker K.B. Casey J.L. Atkins M.B. Toretsky J. Han C. Targeting DDX3X triggers antitumor immunity via a dsrna-mediated tumor-intrinsic type I interferon response.Cancer Res. 2021; 81: 3607-3620https://doi.org/10.1158/0008-5472.can-20-3790Crossref PubMed Google Scholar). However, ISG activation in triple-negative breast cancer cell lines treated with a protein arginine methyltransferase (PRMT) inhibitor, which alters mRNA splicing and induces intronic retention of IR-Alus, was significantly reduced after RIG-I silencing (Wu et al., 2022Wu Q. Nie D.Y. Ba-alawi W. Ji Y. Zhang Z. Cruickshank J. Haight J. Ciamponi F.E. Chen J. Duan S. et al.PRMT inhibition induces a viral mimicry response in triple-negative breast cancer.Nature Chem. Biol. 2022; https://doi.org/10.1038/s41589-022-01024-4Crossref Scopus (6) Google Scholar). More generally, the fact that several types of TEs, including most evolutionarily recent Alu families, are primarily transcribed by RNA polymerase III, which generates uncapped RNA that can retain 5′-PPP moieties, suggests a possible role of RIG-I in sensing these TE families. TLR3, a cell surface and endosomal receptor that can also sense dsRNA, was also shown to sense TE-derived RNA. In human breast cancer cell lines MCF7 (Sheng et al., 2018Sheng W. LaFleur M.W. Nguyen T.H. Chen S. Chakravarthy A. Conway J.R. Li Y. Chen H. Yang H. Hsu P.H. et al.LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade.Cell. 2018; 174: 549-563.e19https://doi.org/10.1016/j.cell.2018.05.052Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar) and MDA-MB-468 (Wu et al., 2022Wu Q. Nie D.Y. Ba-alawi W. Ji Y. Zhang Z. Cruickshank J. Haight J. Ciamponi F.E. Chen J. Duan S. et al.PRMT inhibition induces a viral mimicry response in triple-negative breast cancer.Nature Chem. Biol. 2022; https://doi.org/10.1038/s41589-022-01024-4Crossref Scopus (6) Google Scholar), silencing TLR3 impaired ISG activation induced by the knockdown of LSD1, an epigenetic suppressor of ERVs (Sheng et al., 2018Sheng W. LaFleur M.W. Nguyen T.H. Chen S. Chakravarthy A. Conway J.R. Li Y. Chen H. Yang H. Hsu P.H. et al.LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade.Cell. 2018; 174: 549-563.e19https://doi.org/10.1016/j.cell.2018.05.052Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar) or by the inhibition of PRMT1 (Wu et al., 2022Wu Q. Nie D.Y. Ba-alawi W. Ji Y. Zhang Z. Cruickshank J. Haight J. Ciamponi F.E. Chen J. Duan S. et al.PRMT inhibition induces a viral mimicry response in triple-negative breast cancer.Nature Chem. Biol. 2022; https://doi.org/10.1038/s41589-022-01024-4Crossref Scopus (6) Google Scholar), respectively. Importantly, TLR3 is a sensor found both at the cell surface and in endosomes, and its activation indicates the uptake of TE-derived dsRNA from other cells or translocation of dsRNA from the cytosol into endosomes. A very limited subset of TEs in humans can encode functional reverse transcriptase (RT), including elements from the HERV-K and LINE-1 families. RT expression can lead to the formation of RNA:DNA hybrids and cytosolic DNA, both of which can activate the innate immune sensor cGAS. Binding of cGAS to RNA:DNA hybrids or cDNA of sufficient length induces downstream activation of the adaptor protein stimulator of interferon genes (STING), promoting translocation of IRF3 and NF-κB to the nucleus and the initiation of IFN-I and pro-inflammatory cytokines response. A recent study showed that the cGAS-STING pathway is strongly activated in hyperproliferative cells from the blind mole rat, a species of rodents known for its ability to resist tumor development (Zhao et al., 2021Zhao Y. Oreskovic E. Zhang Q. Lu Q. Gilman A. Lin Y.S. He J. Zheng Z. Lu J.Y. Lee J. et al.Transposon-triggered innate immune response confers cancer resistance to the blind mole rat.Nat. Immunol. 2021; 22: 1219-1230https://doi.org/10.1038/s41590-021-01027-8Crossref PubMed Scopus (18) Google Scholar). Blind mole rats express very low level of DNMT at baseline, and pre-cancerous cells undergoing hyperproliferation further reduce DNA methylation levels, thereby derepressing several TEs, including SINEs, ERVs, and LINEs. These TEs are then reverse-transcribed, forming RNA:DNA hybrids that activate cGAS, inducing an IFN-I-dependent necrotic cell death in hyperplastic premalignant cells and preventing cancer development (Zhao et al., 2021Zhao Y. Oreskovic E. Zhang Q. Lu Q. Gilman A. Lin Y.S. He J. Zheng Z. Lu J.Y. Lee J. et al.Transposon-triggered innate immune response confers cancer resistance to the blind mole rat.Nat. Immunol. 2021; 22: 1219-1230https://doi.org/10.1038/s41590-021-01027-8Crossref PubMed Scopus (18) Google Scholar). In humans, repression of the histone methyltransferase EZH2 in prostate cancer patients correlated with increased ERV expression, and genetic knockout of STING in cell lines significantly prevented IFN-dependent upregulation of major histocompatibility complex (MHC)-I and PD-L1 that followed EZH2 inhibition (Morel et al., 2021Morel K.L. Sheahan A.V. Burkhart D.L. Baca S.C. Boufaied N. Liu Y. Qiu X. Canadas I. Roehle K. Heckler M. et al.EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer.Nature Cancer. 2021; 2: 444-456https://doi.org/10.1038/s43018-021-00185-wCrossref PubMed Scopus (56) Google Scholar). A widespread analysis of TE expression in the Cancer Genome Atlas (TCGA) samples found that stomach, bladder, liver, and head and neck were the cancer types with the most significantly overexpressed TEs compared to matched healthy tissue, indicating that TE expression in tumor is impacted by tissue type (Kong et al., 2019Kong Y. Rose C.M. Cass A.A. Williams A.G. Darwish M. Lianoglou S. Haverty P.M. Tong A.J. Blanchette C. Albert M.L. et al.Transposable element expression in tumors is associated with immune infiltration and increased antigenicity.Nat. Commun. 2019; 10: 5228https://doi.org/10.1038/s41467-019-13035-2Crossref PubMed Scopus (70) Google Scholar). Further, the origin and consequences of innate immune activation will vary depending on the cellular origin of TEs and which TE classes are expressed. Altered TE expression in transformed cells is primarily a consequence of broad dysregulation of epigenetic control mechanisms, making it complex to link general innate immune activation with specific TE classes. Therefore, defining common and specific immunogenic properties of TEs will require careful experimental approaches which connect immunogenic patterns with TE classes, the epigenetic mechanisms controlling their expression, and the pathways they activate. In this context, the aforementioned study performed a correlation analysis of TE upregulation with changes on different cellular pathways, including DNA damage response (DDR) pathway or type I and type II IFN signaling. TEs from the Gypsy, ERVL, and ERV1 families (all members of the LTR/ERV class) showed the strongest positive association with IFN-I response across cancer type, while other families from ERV1, ERV3, and DNA transposons had the highest association with DDR (Kong et al., 2019Kong Y. Rose C.M. Cass A.A. Williams A.G. Darwish M. Lianoglou S. Haverty P.M. Tong A.J. Blanchette C. Albert M.L. et al.Transposable element expression in tumors is associated with immune infiltration and increased antigenicity.Nat. Commun. 2019; 10: 5228https://doi.org/10.1038/s41467-019-13035-2Crossref PubMed Scopus (70) Google Scholar). However, despite the strong correlation across tumor types between ERV expression and immune responses, when both ERVs and Alu elements were induced through inhibition of DNMT1 in patient-derived colorectal cancer cells, Alus were found primarily responsible for dsRNA accumulation and activation of MDA5 (Mehdipour et al., 2020Mehdipour P. Marhon S.A. Ettayebi I. Chakravarthy A. Hosseini A. Wang Y. de Castro F.A. Loo Yau H. Ishak C. Abelson S. et al.Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency.Nature. 2020; 588: 169-173https://doi.org/10.1038/s41586-020-2844-1Crossref PubMed Scopus (63) Google Scholar). In another study, the depletion of MPP8 (a human silencing hub [HUSH] complex component) led to simultaneous expression of LTRs (including ERV9 and HERVH) and LINE1, while LINE1 was the primary driver of the type I IFN response in HEK293 cells (Tunbak et al., 2020Tunbak H. Enriquez-Gasca R. Tie C.H.C. Gould P.A. Mlcochova P. Gupta R.K. Fernandes L. Holt J. van der Veen A.G. Giampazolias E. et al.The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s.Nat. Commun. 2020; 11: 5387https://doi.org/10.1038/s41467-020-19170-5Crossref PubMed Scopus (31) Google Scholar). Finally, Griffin et al. found that widespread induction of several TE families—including SINE, LINE, and a majority of LTR, consecutive to knockout of histone methyltransferase SETDB1—did not induce IFN-I signature in models of murine melanoma and lung carcinoma (Griffin et al., 2021Griffin G.K. Wu J. Iracheta-Vellve A. Patti J.C. Hsu J. Davis T. Dele-Oni D. Du P.P. Halawi A.G. Ishizuka J.J. et al.Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity.Nature. 2021; 595: 309-314https://doi.org/10.1038/s41586-021-03520-4Crossref PubMed Scopus (66) Google Scholar). Altogether, recent results seem to point toward the cancer cell type as a key factor in controlling the immunogenicity of different TE classes and indicate that thorough molecular assays are required to quantify their respective contribution to immune activation. The widespread upregulation of TEs with immunogenic potential during cancer development can at first appear paradoxical, and one could wonder how cancer growth can tolerate innate immune activation. However, while TE expression can lead to the induction of innate immune responses, the activation of these pathways can ultimately have both pro- and anti-tumoral effects. Acute IFN-I induction contributes to increased MHC expression, activation of antigen-presenting cells, and differentiation of CD4+ Th1 cells and promotes CD8+ T cells function and cytotoxicity, all of which are beneficial to stimulating antitumor immune responses. Conversely, IFN-I can also upregulate PD-L1 expression on tumor cells, a key T cell-inhibiting checkpoint, and chronic IFN-I stimulation contributes to CD8+ T cell exhaustion. Further, chronic IFN-I signaling can induce the production of ISGs that promote epithelial-mesenchymal transition, tumor invasion, and metastasis or alter tumor metabolism. Ultimately, either a complete loss or prolonged IFN-I signaling can prove deleterious to the antitumor immune response, highlighting a need for better immunotherapeutic strategies to control IFN-I responses in the TME. Many studies have demonstrated overall beneficial effects of inducing TE expression in tumors (Sheng et al., 2018Sheng W. LaFleur M.W. Nguyen T.H. Chen S. Chakravarthy A. Conway J.R. Li Y. Chen H. Yang H. Hsu P.H. et al.LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade.Cell. 2018; 174: 549-563.e19https://doi.org/10.1016/j.cell.2018.05.052Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar; Kong et al., 2019Kong Y. Rose C.M. Cass A.A. Williams A.G. Darwish M. Lianoglou S. Haverty P.M. Tong A.J. Blanchette C. Albert M.L. et al.Transposable element expression in tumors is associated with immune infiltration and increased antigenicity.Nat. Commun. 2019; 10: 5228https://doi.org/10.1038/s41467-019-13035-2Crossref PubMed Scopus (70) Google Scholar; Choi et al., 2021Choi H. Kwon J. Cho M.S. Sun Y. Zheng X. Wang J. Bouker K.B. Casey J.L. Atkins M.B. Toretsky J. Han C. Targeting DDX3X triggers antitumor immunity via a dsrna-mediated tumor-intrinsic type I interferon response.Cancer Res. 2021; 81: 3607-3620https://doi.org/10.1158/0008-5472.can-20-3790Crossref PubMed Google Scholar; Morel et al., 2021Morel K.L. Sheahan A.V. Burkhart D.L. Baca S.C. Boufaied N. Liu Y. Qiu X. Canadas I. Roehle K. Heckler M. et al.EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer.Nature Cancer. 2021; 2: 444-456https://doi.org/10.1038/s43018-021-00185-wCrossref PubMed Scopus (56) Google Scholar; Zhao et al., 2021Zhao Y. Oreskovic E. Zhang Q. Lu Q. Gilman A. Lin Y.S. He J. Zheng Z. Lu J.Y. Lee J. et al.Transposon-triggered innate immune response confers cancer resistance to the blind mole rat.Nat. Immunol. 2021; 22: 1219-1230https://doi.org/10.1038/s41590-021-01027-8Crossref PubMed Scopus (18) Google Scholar); however there are also discrepancies in the responses to expression of the same TE class in different cell populations or tumor types. This demonstrates a need to further investigate whether anti-tumoral effects of TE expression can be optimized therapeutically by selecting specific locations for TE expression (e.g., preferentially in immune cells vs. tumor cells) or the class of TE expressed and their timing of induction. Further, we still lack a complete understanding of the landscape of immunogenic TEs and what differentiates immunogenic TEs from those that don't trigger an immune response. This will be required to determine whether TEs that are overexpressed in tumors have the potential to stimulate IFN-I responses. Additionally, baseline TE expression in cancer cells and the extent to which cancer cells have adapted to TE expression would impact the cancer-intrinsic and the TME response to TE expression induced by therapy. Tumor specific antigens (TSAs) are peptides bound to MHC presented on the surface of cancer cells and not healthy tissue. TSAs typically result from mutations in cancer cell DNA leading to the synthesis of mutated proteins uniquely expressed in tumor tissue. However, tumor-specificity can also result from the unique expression of non-mutated regions of the genome that are normally silenced, such as TEs, making TE-derived antigens an emerging class of TSAs considered for therapy. Further, despite being characterized as "noncoding" RNA, a subset of TEs contain open reading frames (ORFs), like ORF1/ORF2 within LINE1 elements or the gag, pol, and env genes present in intact ERVs. These protein-coding regions of TEs have the potential to be translated and presented on MHC and serve as targets of antitumor immune responses. Two studies examined two murine cancer cell lines and 26 primary human tumor samples to develop a proteogenomic approach that identifies tumor-specific transcripts that could be translated into novel TSAs (Laumont et al., 2018Laumont C.M. Vincent K. Hesnard L. Audemard E. Bonneil E. Laverdure J.P. Gendron P. Courcelles M. Hardy M.P. Cote C. et al.Noncoding regions are the main source of targetable tumor-specific antigens.Sci. Transl. Med. 2018; 10: eaau5516https://doi.org/10.1126/scitranslmed.aau5516Crossref PubMed Scopus (215) Google Scholar; Ehx et al., 2021Ehx G. Larouche J.D. Durette C. Laverdure J.P. Hesnard L. Vincent K. Hardy M.P. Theriault C. Rulleau C. Lanoix J. et al.Atypical acute myeloid leukemia-specific transcripts generate shared and immunogenic MHC class-I-associated epitopes.Immunity. 2021; 54: 737-752.e10https://doi.org/10.1016/j.immuni.2021.03.001Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). Cancer-specific RNA expression was first identified from RNA-sequencing data by comparing cancer samples to healthy tissue—either thymic epithelial cells (Laumont et al., 2018Laumont C.M. Vincent K. Hesnard L. Audemard E. Bonneil E. Laverdure J.P. Gendron P. Courcelles M. Hardy M.P. Cote C. et al.Noncoding regions are the main source of targetable tumor-specific antigens.Sci. Transl. Med. 2018; 10: eaau5516https://doi.org/10.1126/scitranslmed.aau5516Crossref PubMed Scopus (215) Google Scholar) or hematopoietic progenitors (Ehx et al., 2021Ehx G. Larouche J.D. Durette C. Laverdure J.P. Hesnard L. Vincent K. Hardy M.P. Theriault C. Rulleau C. Lanoix J. et al.Atypical acute myeloid leukemia-specific transcripts generate shared and immunogenic MHC class-I-associated epitopes.Immunity. 2021; 54: 737-752.e10https://doi.org/10.1016/j.immuni.2021.03.001Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). These cancer-specific sequences were then translated in silico across three potential ORFs to create a cancer-specific proteome used as a database for immunopeptidomic mass spectrometry data. Using this approach, the authors identified TSAs originating from noncoding regions of the genome in primary B cell acute lymphoblastic leukemia and lung cancer samples and acute myeloid leukemia (Laumont et al., 2018Laumont C.M. Vincent K. Hesnard L. Audemard E. Bonneil E. Laverdure J.P. Gendron P. Courcelles M. Hardy M.P. Cote C. et al.Noncoding regions are the main source of targetable tumor-specific antigens.Sci. Transl. Med. 2018; 10: eaau5516https://doi.org/10.1126/scitranslmed.aau5516Crossref PubMed Scopus (215) Google Scholar; Ehx et al., 2021Ehx G. Larouche J.D. Durette C. Laverdure J.P. Hesnard L. Vincent K. Hardy M.P. Theriault C. Rulleau C. Lanoix J. et al.Atypical acute myeloid leukemia-specific transcripts generate shared and immunogenic MHC class-I-associated epitopes.Immunity. 2021; 54: 737-752.e10https://doi.org/10.1016/j.immuni.2021.03.001Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). Kong et al. also identified TE-derived peptides presented on MHC using matched transcriptome and immunopeptidome data from a glioblastoma cell line. The authors took a more TE-focused approach, first identifying differentially expressed TE subfamilies in epigenetic drug-treated cell lines from RNA-sequencing, then translating in silico all transcripts from those subfamilies across six ORFs to create their TE-specific database to search immunopeptidomic data (Kong et al., 2019Kong Y. Rose C.M. Cass A.A. Williams A.G. Darwish M. Lianoglou S. Haverty P.M. Tong A.J. Blanchette C. Albert M.L. et al.Transposable element expression in tumors is associated with immune infiltration and increased antigenicity.Nat. Commun. 2019; 10: 5228https://doi.org/10.1038/s41467-019-13035-2Crossref PubMed Scopus (70) Google Scholar). Interestingly, they discovered peptides that originated from SINE-VNTR-Alu elements, which do not contain any previously characterized ORFs, indicating that the presence of known ORFs was not a prerequisite for encoding TE-derived antigens and implying a larger pool of potential antigen-encoding transcripts (Kong et al., 2019Kong Y. Rose C.M. Cass A.A. Williams A.G. Darwish M. Lianoglou S. Haverty P.M. Tong A.J. Blanchette C. Albert M.L. et al.Transposable element expression in tumors is associated with immune infiltration and increased antigenicity.Nat. Commun. 2019; 10: 5228https://doi.org/10.1038/s41467-019-13035-2Crossref PubMed Scopus (70) Google Scholar). Finally, Griffin et al. took yet a different approach, searching RNA-sequencing data for previously annotated TE ORFs and restricting to 8–10mer peptides with predicted MHC binding to use in their immunopeptidomic mass spectrometry search library. This approach allowed the authors to identify TE-encoded peptides presented on MHC in murine cancer cell lines, either present at baseline or upregulated after silencing H3K9 methyltransferase SETDB1 (Griffin et al., 2021Griffin G.K. Wu J. Iracheta-Vellve A. Patti J.C. Hsu J. Davis T. Dele-Oni D. Du P.P. Halawi A.G. Ishizuka J.J. et al.Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity.Nature. 2021; 595: 309-314https://doi.org/10.1038/s41586-021-03520-4Crossref PubMed Scopus (66) Google Scholar). These studies demonstrated that transcripts from non-mutated regions of the genome, including TE, can serve as a source of peptides presented on MHC uniquely on tumor cells. These TSAs serve as attractive targets since their antigenicity does not rely on specific amino acid mutations and therefore can be shared across different tumors from different patients (Ehx et al., 2021Ehx G. Larouche J.D. Durette C. Laverdure J.P. Hesnard L. Vincent K. Hardy M.P. Theriault C. Rulleau C. Lanoix J. et al.Atypical acute myeloid leukemia-specific transcripts generate shared and immunogenic MHC class-I-associated epitopes.Immunity. 2021; 54: 737-752.e10https://doi.org/10.1016/j.immuni.2021.03.001Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). To validate the immunogenicity of TE-derived antigens, Laumont et al. examined frequencies of CD8+ T cells against viral epitopes, TE-derived TSAs, and non-TE-derived TSAs in murine models of colon cancer and lymphoma. In naive mice, while T cells recognizing non-TE-derived TSAs were rare, T cells recognizing TE-derived TSAs had a similar frequency to those specific to viral peptide controls, though relatively few TSAs were examined overall (Laumont et al., 2018Laumont C.M. Vincent K. Hesnard L. Audemard E. Bonneil E. Laverdure J.P. Gendron P. Courcelles M. Hardy M.P. Cote C. et al.Noncoding regions are the main source of targetable tumor-specific antigens.Sci. Transl. Med. 2018; 10: eaau5516https://doi.org/10.1126/scitranslmed.aau5516Crossref PubMed Scopus (215) Google Scholar). In humans, Ehx et al. emphasized the potential immunogenicity of intron-derived TSAs in acute myeloid leukemia. High T cell response to TSAs was predicted by a machine learning model trained on public T cell receptor data, and functional T cell responses were demonstrated by IFNγ secretion and expansion of T cell clones from peripheral blood in response to stimulation with intron-derived TSAs (Ehx et al., 2021Ehx G. Larouche J.D. Durette C. Laverdure J.P. Hesnard L. Vincent K. Hardy M.P. Theriault C. Rulleau C. Lanoix J. et al.Atypical acute myeloid leukemia-specific transcripts generate shared and immunogenic MHC class-I-associated epitopes.Immunity. 2021; 54: 737-752.e10https://doi.org/10.1016/j.immuni.2021.03.001Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). Griffin et al. performed TCR-sequencing and tetramer staining of murine melanoma tumor-infiltrating lymphocytes to show that TE-derived antigen-specific CD8+ T cells upregulated genes associated with T cell activation and cytotoxicity (Griffin et al., 2021Griffin G.K. Wu J. Iracheta-Vellve A. Patti J.C. Hsu J. Davis T. Dele-Oni D. Du P.P. Halawi A.G. Ishizuka J.J. et al.Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity.Nature. 2021; 595: 309-314https://doi.org/10.1038/s41586-021-03520-4Crossref PubMed Scopus (66) Google Scholar). Saini et al. additionally discovered higher T cell reactivity to antigens derived from transcribed ERVs in patients with myeloid malignancies compared to healthy donors (Saini et al., 2020Saini S.K. Orskov A.D. Bjerregaard A.M. Unnikrishnan A. Holmberg-Thyden S. Borch A. Jensen K.V. Anande G. Bentzen A.K. Marquard A.M. et al.Human endogenous retroviruses form a reservoir of T cell targets in hematological cancers.Nat. Commun. 2020; 11: 5660https://doi.org/10.1038/s41467-020-19464-8Crossref PubMed Scopus (26) Google Scholar). Further, they demonstrated functional patient T cell responses targeting ERV peptides presented on MHC, as measured by cytokine release upon co-culture with ERV-peptide-loaded leukemia cells. Finally, it is important to note that TEs are not necessarily transcribed in an autonomous fashion, and a large fraction are found in introns. Moreover, de novo integration of TEs into exons or alternative splicing events allowing readthrough of intronic TEs (Wu et al., 2022Wu Q. Nie D.Y. Ba-alawi W. Ji Y. Zhang Z. Cruickshank J. Haight J. Ciamponi F.E. Chen J. Duan S. et al.PRMT inhibition induces a viral mimicry response in triple-negative breast cancer.Nature Chem. Biol. 2022; https://doi.org/10.1038/s41589-022-01024-4Crossref Scopus (6) Google Scholar) can generate fusion proteins that could serve as targetable antigens. Overall, TEs represent a specific source of immunogenic tumor antigens that can be recognized by T cells and induce a functional response (Laumont et al., 2018Laumont C.M. Vincent K.
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