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1.
Immunity ; 55(3): 527-541.e5, 2022 03 08.
Article in English | MEDLINE | ID: mdl-35231421

ABSTRACT

The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in cancer. Here, we used spatial transcriptomics to examine the nature of B cell responses within TLS in renal cell carcinoma (RCC). B cells were enriched in TLS, and therein, we could identify all B cell maturation stages toward plasma cell (PC) formation. B cell repertoire analysis revealed clonal diversification, selection, expansion in TLS, and the presence of fully mature clonotypes at distance. In TLS+ tumors, IgG- and IgA-producing PCs disseminated into the tumor beds along fibroblastic tracks. TLS+ tumors exhibited high frequencies of IgG-producing PCs and IgG-stained and apoptotic malignant cells, suggestive of anti-tumor effector activity. Therapeutic responses and progression-free survival correlated with IgG-stained tumor cells in RCC patients treated with immune checkpoint inhibitors. Thus, intratumoral TLS sustains B cell maturation and antibody production that is associated with response to immunotherapy, potentially via direct anti-tumor effects.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Tertiary Lymphoid Structures , Carcinoma, Renal Cell/therapy , Female , Humans , Immunoglobulin G , Kidney Neoplasms/therapy , Male , Plasma Cells , Tertiary Lymphoid Structures/pathology , Tumor Microenvironment
2.
Nat Cancer ; 2(8): 794-802, 2021 08.
Article in English | MEDLINE | ID: mdl-35118423

ABSTRACT

Only a minority of patients derive long-term clinical benefit from anti-PD1/PD-L1 monoclonal antibodies. The presence of tertiary lymphoid structures (TLS) has been associated with improved survival in several tumor types. Here, using a large-scale retrospective analysis of three independent cohorts of cancer patients treated with anti-PD1/PD-L1 antibodies, we showed that the presence of mature TLS was associated with improved objective response rate, progression-free survival, and overall survival independently of PD-L1 expression status and CD8+ T-cell density. These results pave the way for using TLS detection to select patients who are more likely to benefit from immune checkpoint blockade.


Subject(s)
Lung Neoplasms , Tertiary Lymphoid Structures , Antibodies, Monoclonal/therapeutic use , B7-H1 Antigen/therapeutic use , Humans , Immune Checkpoint Inhibitors/pharmacology , Lung Neoplasms/drug therapy , Retrospective Studies
3.
Cancer Immunol Immunother ; 68(10): 1561-1572, 2019 Oct.
Article in English | MEDLINE | ID: mdl-31494742

ABSTRACT

Preclinical and clinical studies have suggested that cancer treatment with antitumor antibodies induces a specific adaptive T cell response. A central role in this process has been attributed to CD4+ T cells, but the relevant T cell epitopes, mostly derived from non-mutated self-antigens, are largely unknown. In this study, we have characterized human CD20-derived epitopes restricted by HLA-DR1, HLA-DR3, HLA-DR4, and HLA-DR7, and investigated whether T cell responses directed against CD20-derived peptides can be elicited in human HLA-DR-transgenic mice and human samples. Based on in vitro binding assays to recombinant human MHC II molecules and on in vivo immunization assays in H-2 KO/HLA-A2+-DR1+ transgenic mice, we have identified 21 MHC II-restricted long peptides derived from intracellular, membrane, or extracellular domains of the human non-mutated CD20 protein that trigger in vitro IFN-γ production by PBMCs and splenocytes from healthy individuals and by PBMCs from follicular lymphoma patients. These CD20-derived MHC II-restricted peptides could serve as a therapeutic tool for improving and/or monitoring anti-CD20 T cell activity in patients treated with rituximab or other anti-CD20 antibodies.


Subject(s)
Antigens, CD20/immunology , CD4-Positive T-Lymphocytes/immunology , Lymphoma/drug therapy , Animals , Female , HLA-DRB1 Chains/immunology , Humans , Interferon-gamma/biosynthesis , Lymphoma/immunology , Mice , Rituximab/therapeutic use
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