1. Chemotherapy Drives Tertiary Lymphoid Structures That Correlate with ICI-Responsive TCF1+CD8+ T Cells in Metastatic Ovarian Cancer.
- Author
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Lanickova T, Hensler M, Kasikova L, Vosahlikova S, Angelidou A, Pasulka J, Griebler H, Drozenova J, Mojzisova K, Vankerckhoven A, Laco J, Ryska A, Dundr P, Kocian R, Cibula D, Brtnicky T, Skapa P, Jacob F, Kovar M, Praznovec I, McNeish IA, Halaska MJ, Rob L, Coosemans A, Orsulic S, Galluzzi L, Spisek R, and Fucikova J
- Subjects
- Humans, Female, Paclitaxel administration & dosage, Paclitaxel therapeutic use, Paclitaxel pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols pharmacology, Neoadjuvant Therapy methods, Cystadenocarcinoma, Serous drug therapy, Cystadenocarcinoma, Serous pathology, Cystadenocarcinoma, Serous immunology, Carboplatin administration & dosage, Carboplatin pharmacology, Carboplatin therapeutic use, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating metabolism, Endoplasmic Reticulum Stress drug effects, Endoplasmic Reticulum Stress immunology, Ovarian Neoplasms drug therapy, Ovarian Neoplasms immunology, Ovarian Neoplasms pathology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes drug effects, Tertiary Lymphoid Structures immunology, Tertiary Lymphoid Structures pathology, Immune Checkpoint Inhibitors therapeutic use, Immune Checkpoint Inhibitors pharmacology, Tumor Microenvironment immunology, Tumor Microenvironment drug effects, Hepatocyte Nuclear Factor 1-alpha genetics, Hepatocyte Nuclear Factor 1-alpha metabolism
- Abstract
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., (©2024 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2025
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