In melanoma samples from a clinical trial testing neoadjuvant immune checkpoint blockade (ICB) therapy, RNA sequencing revealed increased expression of B cell-related genes in tumors of ICB-responding patients. Analysis of melanoma data from TCGA mirrored this result and correlated high B cell signatures with improved overall survival. Histological analysis showed a higher density of CD20+ B cells and spatial association with tertiary lymphoid structures in ICB-responding patients. B cells in ICB responders had increased BCR diversity and expression of immune signaling pathways, and displayed a memory rather than naive phenotype.
Contributed by Alex Najibi
ABSTRACT: Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers(1-10) and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity(11-15), although these have been less well-studied in ICB treatment(16). A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling(17) that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter(18)) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.
Author Info: (1) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. bhelmink@mdanderson.org. (2) Department of Breast Medical Oncology, The Un
Author Info: (1) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. bhelmink@mdanderson.org. (2) Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (6) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA. (8) Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA. Broad Institute of the Massachusetts Institute of Technology, Boston, MA, USA. (9) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (10) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (11) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (12) Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (13) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (14) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (15) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (16) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (17) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (18) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (19) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (20) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (21) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (22) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (23) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (24) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (25) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (26) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (27) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (28) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (29) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (30) Department of Thoracic / Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (31) Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (32) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (33) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (34) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (35) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (36) Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (37) Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (38) Nanostring Technologies, Seattle, WA, USA. (39) Nanostring Technologies, Seattle, WA, USA. (40) Nanostring Technologies, Seattle, WA, USA. (41) Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (42) Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (43) Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (44) Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (45) Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (46) Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (47) Departments of Medicine, Surgery, Immunology and Clinical and Translational Science, University of Pittsburgh, Pittsburgh, PA, USA. (48) Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (49) Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (50) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (51) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (52) INSERM, Cordeliers Research Center, Team Cancer, Immune Control and Escape, Paris, France. University Paris Descartes Paris 5, Sorbonne Paris Cite, Centre de Recherche des Cordeliers, Paris, France. Programme Cartes d'Identite des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France. (53) INSERM, Cordeliers Research Center, Team Cancer, Immune Control and Escape, Paris, France. University Paris Descartes Paris 5, Sorbonne Paris Cite, Centre de Recherche des Cordeliers, Paris, France. (54) INSERM, Cordeliers Research Center, Team Cancer, Immune Control and Escape, Paris, France. University Paris Descartes Paris 5, Sorbonne Paris Cite, Centre de Recherche des Cordeliers, Paris, France. (55) Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA. Broad Institute of the Massachusetts Institute of Technology, Boston, MA, USA. (56) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (57) Department of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (58) Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (59) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (60) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. jwargo@mdanderson.org. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. jwargo@mdanderson.org.
