Kasikova et al. leveraged spatial transcriptomics and immunofluorescence microscopy to characterize tertiary lymphoid structures (TLSs) in ovarian carcinoma (OC), finding that mature TLS formation occurred in only 16% of samples and was associated with increased intratumoral effector T cell density. TMB was positively associated with TLS development, and TLS number positively correlated with improved survival. TLSs in OC were relatively deficient in TFH cells and follicular DCs compared to NSCLC, and TLS B cells influenced the checkpoint inhibitor-responsive TCF1+PD1+CD8+ T cell phenotype (more abundant in NSCLC).
Contributed by Morgan Janes
ABSTRACT: Intratumoral tertiary lymphoid structures (TLSs) have been associated with improved outcome in various cohorts of patients with cancer, reflecting their contribution to the development of tumor-targeting immunity. Here, we demonstrate that high-grade serous ovarian carcinoma (HGSOC) contains distinct immune aggregates with varying degrees of organization and maturation. Specifically, mature TLSs (mTLS) as forming only in 16% of HGSOCs with relatively elevated tumor mutational burden (TMB) are associated with an increased intratumoral density of CD8(+) effector T (T(EFF)) cells and TIM3(+)PD1(+), hence poorly immune checkpoint inhibitor (ICI)-sensitive, CD8(+) T cells. Conversely, CD8(+) T cells from immunologically hot tumors like non-small cell lung carcinoma (NSCLC) are enriched in ICI-responsive TCF1(+) PD1(+) T cells. Spatial B-cell profiling identifies patterns of in situ maturation and differentiation associated with mTLSs. Moreover, B-cell depletion promotes signs of a dysfunctional CD8(+) T cell compartment among tumor-infiltrating lymphocytes from freshly isolated HGSOC and NSCLC biopsies. Taken together, our data demonstrate that - at odds with NSCLC - HGSOC is associated with a low density of follicular helper T cells and thus develops a limited number of mTLS that might be insufficient to preserve a ICI-sensitive TCF1(+)PD1(+) CD8(+) T cell phenotype. These findings point to key quantitative and qualitative differences between mTLSs in ICI-responsive vs ICI-irresponsive neoplasms that may guide the development of alternative immunotherapies for patients with HGSOC.
Author Info: (1) Sotio Biotech a.s., Prague, Czech Republic. (2) Sotio Biotech a.s., Prague, Czech Republic. (3) Sotio Biotech a.s., Prague, Czech Republic. (4) Sotio Biotech a.s., Prague, Czec
Author Info: (1) Sotio Biotech a.s., Prague, Czech Republic. (2) Sotio Biotech a.s., Prague, Czech Republic. (3) Sotio Biotech a.s., Prague, Czech Republic. (4) Sotio Biotech a.s., Prague, Czech Republic. Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic. (5) Sotio Biotech a.s., Prague, Czech Republic. (6) Sotio Biotech a.s., Prague, Czech Republic. (7) Department of Pathology, 3rd Faculty of Medicine and University Hospital Kralovske Vinohrady, Prague, Czech Republic. (8) Sotio Biotech a.s., Prague, Czech Republic. (9) Sotio Biotech a.s., Prague, Czech Republic. (10) Sotio Biotech a.s., Prague, Czech Republic. (11) The Fingerland Department of Pathology, Charles University, Faculty of Medicine and University Hospital Hradec Kralove, Hradec Kralove, Czech Republic. (12) The Fingerland Department of Pathology, Charles University, Faculty of Medicine and University Hospital Hradec Kralove, Hradec Kralove, Czech Republic. (13) Department of Pathology, 1st Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic. (14) Department of Gynaecology, Obstetrics and Neonatology, General University Hospital in Prague, 1st Faculty of Medicine, Charles University, Prague, Czech Republic. (15) Department of Gynecology and Obstetrics, 1st Faculty of Medicine, Charles University, University Hospital Bulovka, Prague, Czech Republic. (16) Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic. (17) Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic. (18) Laboratory of Tumor Immunology, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic. (19) Czech Center for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czech Republic. (20) Department of Gynecology and Obstetrics, Charles University, Faculty of Medicine and University Hospital Hradec Kralove, Hradec Kralove, Czech Republic. (21) Department of Pneumology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic. (22) Department of Thoracic Surgery, Charles University, 3rd Faculty of Medicine and Thomayer University Hospital, Prague, Czech Republic. (23) Departments of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, West Hollywood, CA, USA. (24) 3rd Department of Surgery, First Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic. (25) Oncology and Pneumology Department, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic. (26) 3rd Department of Surgery, First Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic. (27) Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland. (28) Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland. (29) Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK. (30) Department of Gynecology and Obstetrics, Charles University, 3rd Faculty of Medicine and University Hospital Kralovske Vinohrady, Prague, Czech Republic. (31) Department of Gynecology and Obstetrics, Charles University, 3rd Faculty of Medicine and University Hospital Kralovske Vinohrady, Prague, Czech Republic. (32) Department of Gynaecology, Obstetrics and Neonatology, General University Hospital in Prague, 1st Faculty of Medicine, Charles University, Prague, Czech Republic. (33) Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. (34) Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA. Sandra and Edward Meyer Cancer Center, New York, NY, USA. Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA. (35) Sotio Biotech a.s., Prague, Czech Republic. Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic. (36) Sotio Biotech a.s., Prague, Czech Republic. fucikova@sotio.com. Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic. fucikova@sotio.com.
