Chemotherapy Drives Tertiary Lymphoid Structures That Correlate with ICI-Responsive TCF1+CD8+ T Cells in Metastatic Ovarian Cancer

. 2025 Jan 06 ; 31 (1) : 164-180.

Jazyk angličtina Země Spojené státy americké Médium print

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/pmid39163092

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

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 Gynaecology Obstetrics and Neonatology General University Hospital Prague 1st Faculty of Medicine Charles University Prague Czech Republic

Department of Gynecology and Obstetrics 1st Faculty of Medicine Charles University University Hospital Bulovka Prague Czech Republic

Department of Gynecology and Obstetrics Charles University 3rd Faculty of Medicine and University Hospital Kralovske Vinohrady Prague Czech Republic

Department of Gynecology and Obstetrics Charles University Faculty of Medicine and University Hospital Hradec Kralove Hradec Kralove Czech Republic

Department of Immunology Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Obstetrics and Gynecology David Geffen School of Medicine University of California Los Angeles Los Angeles California

Department of Pathology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Pathology 3rd Faculty of Medicine and University Hospital Kralovske Vinohrady Prague Czech Republic

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Radiation Oncology Weill Cornell Medical College New York New York

Department of Surgery and Cancer Ovarian Cancer Action Research Centre Imperial College London London United Kingdom

Department of Veterans Affairs Greater Los Angeles Healthcare System Los Angeles California

Laboratory of Tumor Immunology and Immunotherapy Department of Oncology Leuven Cancer Institute KU Leuven Leuven Belgium

Laboratory of Tumor Immunology Institute of Microbiology of the Czech Academy of Sciences Prague Czech Republic

Ovarian Cancer Research Department of Biomedicine University Hospital Basel and University of Basel Basel Switzerland

Sandra and Edward Meyer Cancer Center New York New York

Sotio Biotech Prague Czech Republic

The Fingerland Department of Pathology Charles University Faculty of Medicine in Hradec Kralove and University Hospital Hradec Kralove Hradec Kralove Czech Republic

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