Breaching B cell tolerance in the tumor microenvironment

Banville, Allyson C; Nelson, Brad H.

doi:10.1016/j.ccell.2022.03.011

Cited by 2 publications

(2 citation statements)

References 9 publications

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“…Expression of Ag and production of AAb, regardless of disease stage, suggested that the AAbidentified tumor-associated Ags are not lost to immunoediting. In addition to expression, our finding that AAbs target PTM epitopes adds to the growing body of evidence that tumor-specific AAbs predominantly recognize nonmutated self-proteins (41)(42)(43). We were able to identify immunogenic PTMs to three of our tumor-specific AAbs, but more likely exist because we only screened for a few probable PTM modifications and only at predicted sites.…”

Section: Discussionmentioning

confidence: 82%

Posttranslational modifications induce autoantibodies with risk prediction capability in patients with small cell lung cancer

et al. 2023

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Small cell lung cancer (SCLC) elicits the generation of autoantibodies that result in unique paraneoplastic neurological syndromes. The mechanistic basis for the formation of such autoantibodies is largely unknown but is key to understanding their etiology. We developed a high-dimensional technique that enables detection of autoantibodies in complex with native antigens directly from patient plasma. Here, we used our platform to screen 1009 human plasma samples for 3600 autoantibody-antigen complexes, finding that plasma from patients with SCLC harbors, on average, fourfold higher disease-specific autoantibody signals compared with plasma from patients with other cancers. Across three independent SCLC cohorts, we identified a set of common but previously unknown autoantibodies that are produced in response to both intracellular and extracellular tumor antigens. We further characterized several disease-specific posttranslational modifications within extracellular proteins targeted by these autoantibodies, including citrullination, isoaspartylation, and cancer-specific glycosylation. Because most patients with SCLC have metastatic disease at diagnosis, we queried whether these autoantibodies could be used for SCLC early detection. We created a risk prediction model using five autoantibodies with an average area under the curve of 0.84 for the three cohorts that improved to 0.96 by incorporating cigarette smoke consumption in pack years. Together, our findings provide an innovative approach to identify circulating autoantibodies in SCLC with mechanistic insight into disease-specific immunogenicity and clinical utility.

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Section: Discussionmentioning

confidence: 82%

Posttranslational modifications induce autoantibodies with risk prediction capability in patients with small cell lung cancer

et al. 2023

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“…Additionally, potential biomarkers like PD-L1 expression, tumour mutational burden and TILs have yet to be proven predictive for patient selection 10 . Although the presence and state of TILs in OC have been extensively explored in previous studies [11][12][13][14] , recent research has shed light on the involvement of additional immune cell types in sculpting the tumour microenvironment (TME) of OC [15][16][17][18] . However, a comprehensive understanding of the temporal evolution of immune cell infiltration and its spatial organization in the recurrent disease setting is still lacking 13 .…”

Section: Introductionmentioning

confidence: 99%

Myeloid cell networks determine reinstatement of original immune environments in recurrent ovarian cancer

Ghisoni,

Benedetti,

Minasyan

et al. 2024

Preprint

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Immunotherapy has produced disappointing results in recurrent ovarian cancer (OC). However, the prognostic value of tumour-infiltrating lymphocytes (TILs) is largely based on the analysis of treatment-naive tumours. To understand the immunobiology of recurrent cancers, and their evolution, we profiled 170 patient-matched primary-recurrent OC samples from 69 patients of two independent cohorts. By capturing heterogeneous TIL distributions, we identified four immune phenotypes associated with differential prognosis, TILs states and TILs:myeloid networks, which dictate malignant evolution after chemotherapy and recurrence. Notably, recurrent tumours recapitulate the immunogenic patterns of original cancers. Mirroring inflamed human OC, preclinical recurrent Brca1mut tumours maintained activated TILs:dendritic cells (DCs) niches and immunostimulatory tumour-associated macrophages (TAMs). Conversely, recurrent Brca1wt tumours displayed loss of TILs:DCs niches and accumulated immunosuppressive myeloid networks featuring Trem2/ApoEhigh TAMs and Nduf4l2high/Galectin3high malignant states. Our study highlights that persistent immunogenicity in recurrent OC is governed by the crosstalk between dissimilar myeloid cells and TILs, which is BRCA-dependent.

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Breaching B cell tolerance in the tumor microenvironment

Cited by 2 publications

References 9 publications

Posttranslational modifications induce autoantibodies with risk prediction capability in patients with small cell lung cancer

Posttranslational modifications induce autoantibodies with risk prediction capability in patients with small cell lung cancer

Myeloid cell networks determine reinstatement of original immune environments in recurrent ovarian cancer

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