B cells and tertiary lymphoid structures promote immunotherapy response

By Beth A. Helmink, S. Reddy, Jianjun Gao, Shaojun Zhang, R. Başar, R. Thakur, K. Yizhak, Moshe Sade-Feldman, J. Blando, Guangchun Han and 50 more. Nature, 2020

2,250 citations recorded by the source corpus.

Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1–10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11–15, although these have been less well-studied in ICB treatment16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 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-counter18) 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. Multiomic profiling of several cohorts of patients treated with immune checkpoint blockade highlights the presence and potential role of B cells and tertiary lymphoid structures in promoting therapy response.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/c19a9cb99f887b1515d53bfa9d9740044f8f0b32

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Citations in the corpus

Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition (2021, neutral): “The selective expression of CCR5 and CXCL13 in neoantigen-specific T cells further suggests that a key feature of CPI-responsiveness is the ability to sustain ongoing priming and recruitment of tumour reactive T cells supported by CXCR5+ lymphocytes, which may include T and B cells (Helmink et al., ”
Tumor-infiltrating lymphocytes in the immunotherapy era (2020, background): “Increased BCR diversity and clonal expansion were also observed in tumors of melanoma patients.(75) Of note, some autoantibodies have also been found to be tumor promoting.”
Tertiary lymphoid structures in cancer (2022, background): “Although a number of observations are consistentwith a model in which ICB affects TLS functionality (15, 136, 137), the evidence is still circumstantial.”
Coordinated Cellular Neighborhoods Orchestrate Antitumoral Immunity at the Colorectal Cancer Invasive Front (2019, background): “The biological and clinical relevance of TLSs has been demonstrated not only in CRC but also in multiple other cancers (Binnewies et al., 2018; Cabrita et al., 2020; Di Caro et al., 2014; Dieu-Nosjean et al., 2016; Graham and Appelman, 1990; Helmink et al., 2020; Petitprez et al., 2020; Sautès-Fridm”
Spatially organized multicellular immune hubs in human colorectal cancer (2021, background): “, 2016), contain germinal center B cells, and have been associated with high T cell activity, favorable prognosis, and effective response to immunotherapy (Cabrita et al., 2020; Coppola et al., 2011; Helmink et al., 2020; Petitprez et al., 2020; Sautès-Fridman et al., 2019).”
Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers (2020, result): “This finding is in accordance with studies demonstrating that tumor-infiltrating and systemic B cell responses are both predictive and indicative of responses to immunotherapy (Helmink et al., 2020).”