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Chemotherapy Drives Tertiary Lymphoid Structures That Correlate with ICI-Responsive TCF1+CD8+ T Cells in Metastatic Ovarian Cancer
T. Lanickova, M. Hensler, L. Kasikova, S. Vosahlikova, A. Angelidou, J. Pasulka, H. Griebler, J. Drozenova, K. Mojzisova, A. Vankerckhoven, J. Laco, A. Ryska, P. Dundr, R. Kocian, D. Cibula, T. Brtnicky, P. Skapa, F. Jacob, M. Kovar, I....
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
Grantová podpora
I01 BX004974
BLRD VA - United States
R01 CA103924
NCI NIH HHS - United States
R01 CA208753
NCI NIH HHS - United States
U54 CA274291
NCI NIH HHS - United States
I01 BX006020
BLRD VA - United States
R01 CA271915
NCI NIH HHS - United States
NLK
Freely Accessible Science Journals
od 1995
Open Access Digital Library
od 1995-01-01
Open Access Digital Library
od 1995-01-01
- MeSH
- CD8-pozitivní T-lymfocyty * imunologie účinky léků MeSH
- ektopické lymfoidní struktury * imunologie patologie MeSH
- hepatocytární jaderný faktor 1-alfa * genetika metabolismus MeSH
- inhibitory kontrolních bodů * terapeutické užití farmakologie MeSH
- karboplatina aplikace a dávkování farmakologie terapeutické užití MeSH
- lidé MeSH
- nádorové mikroprostředí * imunologie účinky léků MeSH
- nádory vaječníků * farmakoterapie imunologie patologie MeSH
- neoadjuvantní terapie metody MeSH
- paclitaxel aplikace a dávkování terapeutické užití farmakologie MeSH
- protokoly protinádorové kombinované chemoterapie terapeutické užití farmakologie MeSH
- serózní cystadenokarcinom farmakoterapie patologie imunologie MeSH
- stres endoplazmatického retikula účinky léků imunologie MeSH
- tumor infiltrující lymfocyty imunologie účinky léků metabolismus MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICI) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication. EXPERIMENTAL DESIGN: We harnessed a variety of transcriptomic, spatial, and functional assays to characterize the differential impact of neoadjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to neoadjuvant chemotherapy (NACT)-naïve HGSOC samples from five independent patient cohorts. RESULTS: We found NACT-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD1+ CD8+ T cells over their ICI-insensitive TIM-3+PD1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden. CONCLUSIONS: Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC. See related commentary by Bravo Melgar and Laoui, p. 10.
Caryl and Israel Englander Institute for Precision Medicine New York New York
Department of Radiation Oncology Weill Cornell Medical College New York New York
Department of Veterans Affairs Greater Los Angeles Healthcare System Los Angeles California
Sandra and Edward Meyer Cancer Center New York New York
Citace poskytuje Crossref.org
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