Intratumoral Heterogeneity in Cancer/testis Antigen Expression in Solid Tumors, Implications for Cancer Immunotherapy

Mie Killerich Jakobsen

doi:10.21996/f0yf-xf41

Intratumoral Heterogeneity in Cancer/testis Antigen Expression in Solid Tumors, Implications for Cancer Immunotherapy

Publikation: Afhandling › Ph.d.-afhandling

Abstract

Epigenetiske ændringer, herunder ændringer i DNA-methylering, udgør fundamentale karakteristika ved cancerceller. Disse cancer-relaterede ændringer i methyleringsmønstre kan medføre genomisk ustabilitet, øget ekspression af antigener, som normalt ikke udtrykkes i raskt somatisk væv, såsom cancer/testis-antigener (CTAer), samt nedsat ekspression af tumorsuppressor gener. På grund af deres hyppige og specifikke ekspression i cancerceller anses CTAer for lovende mål for immunterapeutisk behandling af solide tumorer. Dog kan variabiliteten i CTA-ekspressionen mellem forskellige tumorer og selv mellem cancerceller inden for samme tumor føre til at CTA-negative cancerceller undslipper den målrettede behandling. Behandling med DNA-methyltransferase-hæmmere (DNMT-hæmmere) er blevet foreslået til at øge CTA-ekspressionen blandt cancerceller og dermed forbedre effektiviteten af CTA-målrettede immunterapier. Desuden har monoterapi med DNMT-hæmmere vist sig at være effektiv til behandling af hæmatologiske cancere, men denne effektivitet er endnu ikke blevet udvidet til behandling af solide tumorer.

Formålet med mit projekt var at udforske potentialet for CTAer som mål for immunterapeutisk behandling af solide tumorer samt at undersøge effekten af DNMThæmmere til at opregulere CTA-ekspression og som monoterapi til solide tumorer. Vi undersøgte ekspressionen af CTAet VCX2 i forskellige typer af normalt og malignt væv og fandt, at VCX2 kun blev udtrykt i et lille antal modermærkekræptumorer og at VCX2- ekspressionen var tumor-specifik. Desuden kunne VCX2-ekspressionen øges ved behandling med DNMT-hæmmere og yderligere opreguleres ved kombinationsbehandling med DNMThæmmere og histondeacetylase-hæmmere (HDAC-hæmmere). Dog er VCX2 alene ikke egnet som mål for immunterapi; i stedet kunne det inkluderes i et panel af CTAer til immunterapeutiske strategier rettet mod flere CTAer, såsom vacciner, til behandling af VCX2- positive modermærkekræptumorer. Derudover afslørede målrettet enkeltcelle-mRNAsekventering (scRNAseq) af primære modermærkekræpcellekulturer og celler fra friske lungeadenokarcinomer en tidligere ukendt variabilitet i CTA-ekspression inden for disse cancertyper, hvilket kan have betydning for udviklingen af fremtidige immunterapeutiske strategier rettet mod disse antigener. Homogen ekspression af individuelle CTAer var et sjældent fænomen, kun observeret i modermærkekræpceller, hvilket understreger vigtigheden af immunterapeutiske tilgange, der retter sig mod flere CTAer for at forhindre undvigelse af CTA-negative cancerceller. Desuden viste scRNAseq af brystkræpcellelinjer en meget variabel respons på DNMT-hæmmer-behandling, hvilket kunne mindskes ved kombinationsbehandling med DNMT-hæmmere og HDAC-hæmmere. Dette antyder, at denne kombinationsbehandling kunne forbedre den kliniske effektivitet af epigenetisk behandling af solide tumorer og mindske variabiliteten i CTA-ekspression, hvilket igen kunne forbedre effektiviteten af CTA-rettede immunterapier. Vores resultater understreger vigtigheden af at karakterisere patienttumorer på enkeltcelle-niveau for at udvælge passende CTA-mål for personaliseret immunterapeutisk behandling af patienter med solide tumorer.

Originalsprog	Engelsk
Bevilgende institution	Syddansk Universitet
Vejledere/rådgivere	Gjerstorff, Morten Frier, Hovedvejleder Ditzel, Henrik Jørn, Bivejleder Barington, Torben, Bivejleder
Dato for forsvar	28. jun. 2024
Udgiver	Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
DOI	https://doi.org/10.21996/f0yf-xf41
Status	Udgivet - 24. maj 2024

Note vedr. afhandling

Afhandlingen kan læses på SDUs bibliotek. 

Dokumenter og links

10.21996/f0yf-xf41

Dokument under embargo

Ph.D._thesis_-_Mie_Kiilerich_Jakobsen
Forlagets udgivne version, 40 MB
Embargo slutter: 24/05/2025

1 Tidsskriftartikel
1 Kommentar/debat

The Cancer/Testis Antigen Gene VCX2 Is Rarely Expressed in Malignancies but Can Be Epigenetically Activated Using DNA Methyltransferase and Histone Deacetylase Inhibitors
Jakobsen, M. K., Traynor, S., Stæhr, M., Duijf, P. G., Nielsen, A. Y., Terp, M. G., Pedersen, C. B., Guldberg, P., Ditzel, H. J. & Gjerstorff, M. F., 9. feb. 2021, I: Frontiers in Oncology. 10, 12 s., 584024.
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Åben adgang
Fil
57 Downloads (Pure)
CAR T-Cell Cancer Therapy Targeting Surface Cancer/Testis Antigens
Jakobsen, M. K. & Gjerstorff, M. F., 2. sep. 2020, I: Frontiers in Immunology. 11, 7 s., 1568.
Publikation: Bidrag til tidsskrift › Kommentar/debat › Forskning › peer review

Åben adgang
Fil

94 Downloads (Pure)

Citationsformater

@misc{a3e52c08db764aada064ba02ee12bb50,

title = "Intratumoral Heterogeneity in Cancer/testis Antigen Expression in Solid Tumors, Implications for Cancer Immunotherapy",

abstract = "Epigenic alterations, including changes in DNA methylation, are fundamental characteristics of cancer cells. These cancer-related changes in methylation patterns can result in genomic instability, increased expression of antigens typically not expressed in healthy somatic tissue, such as cancer/testis antigens (CTAs), and decreased expression of tumor suppressor genes. Due to their frequent and specific expression in cancer cells, CTAs are considered promising targets for immunotherapeutic treatment of solid cancers. However, the variability in CTA expression among different tumors and even between cancer cells within the same tumor can lead to escape of CTA-negative cancer cells when targeting these antigens with immunotherapy. Treatment with DNA methyltransferase inhibitors (DNMTis) has been proposed to increase CTA expression among cancer cells, potentially enhancing the effectiveness of CTA-directed immunotherapies. Further, DNMTi monotherapy has shown efficacy in treating hematological cancers, however, this effectiveness has not been expanded to treatment of solid cancers.The aim of my project was to further explore the potential of CTAs as targets for immunotherapeutic treatment of solid cancers and to investigate the use of DNMTi treatment for upregulation of CTA expression and as a monotherapy for solid cancers. We examined the expression of the CTA VCX2 in various types of normal and malignant Qssues and found that VCX2 was only expressed in a small number of melanoma tumors and that VCX2 expression was highly tumor specific. Furthermore, VCX2 expression could be upregulated by treatment with a DNMTis and further augmented by combination treatment with DNMTis and histone deacetylase inhibitors (HDACis). However, VCX2 alone may not be suitable as a target for immunotherapy; instead, it could be included in a panel of CTAs for multitargeting immunotherapies, such as vaccines, for the treatment of VCX2-posiQve melanoma tumors. Additionally, targeted single-cell mRNA sequencing (scRNAseq) of primary melanoma cell cultures and cells from fresh lung adenocarcinomas, revealed a previously unrecognized variability in CTA expression within these cancer types, which could have implications for the development of future immunotherapeutic strategies targeting these antigens. Homogeneous expression of individual CTAs was rare, observed only in melanoma, emphasizing the importance of immunotherapeutic approaches targeting multiple CTAs to prevent evasion by CTA-negative subclones. Furthermore, scRNAseq of breast cancer cell lines demonstrated a highly variable response to DNMTi treatment, which could be mitigated by combination treatment with DNMTis and HDACis. This suggests that this combination treatment could enhance the clinical effectiveness of epigenetic treatment of solid cancers and minimize variability in CTA expression, thereby improving the efficacy of CTA-directed immunotherapies. Our results underscore the importance of characterizing patient tumors at the single-cell level to select appropriate CTA targets for personalized immunotherapeutic treatment of patients with solid tumors.",

author = "Jakobsen, {Mie Killerich}",

year = "2024",

month = may,

day = "24",

doi = "10.21996/f0yf-xf41",

language = "English",

publisher = "Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet",

school = "SDU",

}

TY - GEN

T1 - Intratumoral Heterogeneity in Cancer/testis Antigen Expression in Solid Tumors, Implications for Cancer Immunotherapy

AU - Jakobsen, Mie Killerich

PY - 2024/5/24

Y1 - 2024/5/24

N2 - Epigenic alterations, including changes in DNA methylation, are fundamental characteristics of cancer cells. These cancer-related changes in methylation patterns can result in genomic instability, increased expression of antigens typically not expressed in healthy somatic tissue, such as cancer/testis antigens (CTAs), and decreased expression of tumor suppressor genes. Due to their frequent and specific expression in cancer cells, CTAs are considered promising targets for immunotherapeutic treatment of solid cancers. However, the variability in CTA expression among different tumors and even between cancer cells within the same tumor can lead to escape of CTA-negative cancer cells when targeting these antigens with immunotherapy. Treatment with DNA methyltransferase inhibitors (DNMTis) has been proposed to increase CTA expression among cancer cells, potentially enhancing the effectiveness of CTA-directed immunotherapies. Further, DNMTi monotherapy has shown efficacy in treating hematological cancers, however, this effectiveness has not been expanded to treatment of solid cancers.The aim of my project was to further explore the potential of CTAs as targets for immunotherapeutic treatment of solid cancers and to investigate the use of DNMTi treatment for upregulation of CTA expression and as a monotherapy for solid cancers. We examined the expression of the CTA VCX2 in various types of normal and malignant Qssues and found that VCX2 was only expressed in a small number of melanoma tumors and that VCX2 expression was highly tumor specific. Furthermore, VCX2 expression could be upregulated by treatment with a DNMTis and further augmented by combination treatment with DNMTis and histone deacetylase inhibitors (HDACis). However, VCX2 alone may not be suitable as a target for immunotherapy; instead, it could be included in a panel of CTAs for multitargeting immunotherapies, such as vaccines, for the treatment of VCX2-posiQve melanoma tumors. Additionally, targeted single-cell mRNA sequencing (scRNAseq) of primary melanoma cell cultures and cells from fresh lung adenocarcinomas, revealed a previously unrecognized variability in CTA expression within these cancer types, which could have implications for the development of future immunotherapeutic strategies targeting these antigens. Homogeneous expression of individual CTAs was rare, observed only in melanoma, emphasizing the importance of immunotherapeutic approaches targeting multiple CTAs to prevent evasion by CTA-negative subclones. Furthermore, scRNAseq of breast cancer cell lines demonstrated a highly variable response to DNMTi treatment, which could be mitigated by combination treatment with DNMTis and HDACis. This suggests that this combination treatment could enhance the clinical effectiveness of epigenetic treatment of solid cancers and minimize variability in CTA expression, thereby improving the efficacy of CTA-directed immunotherapies. Our results underscore the importance of characterizing patient tumors at the single-cell level to select appropriate CTA targets for personalized immunotherapeutic treatment of patients with solid tumors.

AB - Epigenic alterations, including changes in DNA methylation, are fundamental characteristics of cancer cells. These cancer-related changes in methylation patterns can result in genomic instability, increased expression of antigens typically not expressed in healthy somatic tissue, such as cancer/testis antigens (CTAs), and decreased expression of tumor suppressor genes. Due to their frequent and specific expression in cancer cells, CTAs are considered promising targets for immunotherapeutic treatment of solid cancers. However, the variability in CTA expression among different tumors and even between cancer cells within the same tumor can lead to escape of CTA-negative cancer cells when targeting these antigens with immunotherapy. Treatment with DNA methyltransferase inhibitors (DNMTis) has been proposed to increase CTA expression among cancer cells, potentially enhancing the effectiveness of CTA-directed immunotherapies. Further, DNMTi monotherapy has shown efficacy in treating hematological cancers, however, this effectiveness has not been expanded to treatment of solid cancers.The aim of my project was to further explore the potential of CTAs as targets for immunotherapeutic treatment of solid cancers and to investigate the use of DNMTi treatment for upregulation of CTA expression and as a monotherapy for solid cancers. We examined the expression of the CTA VCX2 in various types of normal and malignant Qssues and found that VCX2 was only expressed in a small number of melanoma tumors and that VCX2 expression was highly tumor specific. Furthermore, VCX2 expression could be upregulated by treatment with a DNMTis and further augmented by combination treatment with DNMTis and histone deacetylase inhibitors (HDACis). However, VCX2 alone may not be suitable as a target for immunotherapy; instead, it could be included in a panel of CTAs for multitargeting immunotherapies, such as vaccines, for the treatment of VCX2-posiQve melanoma tumors. Additionally, targeted single-cell mRNA sequencing (scRNAseq) of primary melanoma cell cultures and cells from fresh lung adenocarcinomas, revealed a previously unrecognized variability in CTA expression within these cancer types, which could have implications for the development of future immunotherapeutic strategies targeting these antigens. Homogeneous expression of individual CTAs was rare, observed only in melanoma, emphasizing the importance of immunotherapeutic approaches targeting multiple CTAs to prevent evasion by CTA-negative subclones. Furthermore, scRNAseq of breast cancer cell lines demonstrated a highly variable response to DNMTi treatment, which could be mitigated by combination treatment with DNMTis and HDACis. This suggests that this combination treatment could enhance the clinical effectiveness of epigenetic treatment of solid cancers and minimize variability in CTA expression, thereby improving the efficacy of CTA-directed immunotherapies. Our results underscore the importance of characterizing patient tumors at the single-cell level to select appropriate CTA targets for personalized immunotherapeutic treatment of patients with solid tumors.

U2 - 10.21996/f0yf-xf41

DO - 10.21996/f0yf-xf41

M3 - Ph.D. thesis

PB - Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet

ER -

Intratumoral Heterogeneity in Cancer/testis Antigen Expression in Solid Tumors, Implications for Cancer Immunotherapy

Abstract

Note vedr. afhandling

Dokumenter og links

Dokument under embargo

Fingeraftryk

Relaterede publikationer

The Cancer/Testis Antigen Gene VCX2 Is Rarely Expressed in Malignancies but Can Be Epigenetically Activated Using DNA Methyltransferase and Histone Deacetylase Inhibitors

CAR T-Cell Cancer Therapy Targeting Surface Cancer/Testis Antigens

Citationsformater