Aging-associated and CD4 T-cell–dependent ectopic CXCL13 activation predisposes to anti–PD-1 therapy-induced adverse events

Tsukamoto, Hirotake; Komohara, Yoshihiro; Tomita, Yusuke; Miura, Yuji; Motoshima, Takanobu; Imamura, Kosuke; Kimura, Toshiki; Ikeda, Tokunori; Fujiwara, Yukio; Yano, Hiromichi; Kamba, Tomomi; Sakagami, Takuro; Oshiumi, Hiroyuki

doi:10.1073/pnas.2205378119

Cited by 25 publications

(18 citation statements)

References 48 publications

(83 reference statements)

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“…We were not able to reproduce these findings, but this may be due to different timing in blood collection and B cells migrating quickly into peripheral tissues following activation. A recent study found that aged anti-PD-1-treated mice developed TLS-like aggregates in irAE-affected tissue in a CXCL13-dependent fashion and that B cell depletion could attenuate ICI-inflicted toxicity [48]. So far, the use of rituximab for irAE management is limited to case reports [49].…”

Section: Discussionmentioning

confidence: 99%

Toxicity-specific peripheral blood T and B cell dynamics in anti-PD-1 and combined immune checkpoint inhibition

Eijs

Verheijden

Wees

et al. 2023

Preprint

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Background Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape of advanced malignancies, but come with a diverse spectrum of immune-related adverse events (irAEs). Studies into irAE mechanisms are needed to make a transition from expert-opinion to evidence-based irAE treatment strategies. Methods We aimed to longitudinally characterize peripheral blood T and B cell dynamics in ICI-treated patients developing irAEs and remaining irAE-free. PBMCs were immunophenotyped and functionally assessed with multicolor flow cytometry at baseline, after ±3 weeks and ±6 weeks or upon clinically relevant irAEs. Additionally, serum cytokine concentrations for 23 analytes were measured by multiplex immunoassay at the same timepoints. Results We analyzed samples from 44 ICI-treated patients (24 anti-PD-1 monotherapy, 20 combined anti-PD-1 and anti-CTLA-4; cICI), of whom 22 developed clinically relevant irAEs, and 10 healthy donors. IrAEs after cICI were characterized by significantly enhanced proliferation of Th1-associated, mainly effector memory T cells, as well as Th17-associated and possibly antibody-mediated immune responses. The latter response was reflected in cICI toxicity by rising CXCL13 and IL-21 levels, but without changes in CD21lo, memory, class-switched or newly activated B cell subsets. Anti-PD-1 monotherapy-inflicted irAEs were associated with a modestly enhanced Th1-associated response compared to irAE-free patients, only reflected by increasing serum CXCL9 and CXCL10, but without cellular changes in Th1/Tc1 subsets. PD-1+LAG-3+double-positive (DP) CD8+T cells retained their proinflammatory potential in all treatment groups, regardless of irAE development. Especially DP CD8+T cells showed enhanced cytotoxic capacity in patients with irAEs after cICI. In all patients with irAEs, highly cytotoxic CD57+CD8+T cells were abundant. Conclusions Peripheral blood immune responses are substantially different between cICI and anti-PD-1 monotherapy-treated patients. ICI-induced toxicity is clearly dominated by an enhanced Th1-associated response, but in cICI we also found evidence for Th17-associated and possibly antibody-mediated responses. CD4+effector memory T cells were the principal cycling cells in irAEs after cICI. Together, our data add to the growing body of evidence that irAEs may be antibody-mediated and driven by newly activated CD4+helper T cells, specifically after cICI.

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Section: Discussionmentioning

confidence: 99%

Toxicity-specific peripheral blood T and B cell dynamics in anti-PD-1 and combined immune checkpoint inhibition

Eijs

Verheijden

Wees

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…In addition to higher levels of CXCL10, activation of other basal autoimmune factors, such as production of organ‐specific autoantibodies, 12 dominance of specific T‐cell receptor repertoires, 22 or genetic and environmental factors, could potentially predispose individuals to the development of irAEs in local organs. Our previous study found a clear association between systemically higher CXCL13 levels and irAE occurrence in patients who received ICIs 21 . Moreover, in ICI‐treated aged mice, we demonstrated that CXCL13 was responsible for aberrant tertiary lymphoid structure generation in irAE‐affected organs 21 .…”

Section: Discussionmentioning

confidence: 56%

Predictive value of CXCL10 for the occurrence of immune‐related adverse events in patient with renal cell carcinoma

Miura

Motoshima

Anami

et al. 2023

Microbiology and Immunology

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Immune checkpoint inhibitors (ICIs) have recently improved the prognosis of various cancers. By contrast, some immune-related adverse events (irAEs) caused by ICIs are fatal and have become problematic. The pathogenesis of irAEs remains unknown and must be elucidated to establish biomarkers. This study investigated plasma cytokine, chemokine, and anti-CD74 autoantibody levels in patients with renal cell carcinoma (RCC) and analyzed their association with irAEs. In a discovery cohort of 13 patients, plasma levels of chemokine (C-X-C motif) ligand (CXCL) 1, IL-17A, IL-1β, IL-6, IL-8, CXCL10, MCP-1, and TNFα were measured at baseline and post-dose 1. Only CXCL10, at post-dose 1 but not at baseline, was significantly associated with grade 2 or higher irAEs (P = 0.0413). Plasma CXCL10 levels were then measured at baseline and post-dose 1 in an extended cohort of 43 patients with RCC who received ICIbased treatment. Higher plasma CXCL10 levels both at baseline and post-dose1 were significantly associated with the occurrence of grade 2 or higher irAEs (P = 0.0246 and 0.0137, respectively). Plasma CXCL13 levels, which we measured in a previous study, were significantly higher in patients with grade 2 or higher irAEs at baseline but not at post-dose 1 (P = 0.0037 and 0.052, respectively). No significant association between plasma anti-CD74 autoantibody level and both irAE pneumonitis and any grade 2 or higher irAE was observed. In conclusion, plasma CXCL10 is significantly associated with the occurrence of irAEs in patients with RCC treated with ICIs. CXCL10 is a potential predictive and ontreatment biomarker for irAEs.

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“…The expression level of CXCL13 has been found linked to the proinflammatory features of macrophages, could predict the response to the combination of chemotherapy with checkpoint inhibitors for TNBCs [40]. Moreover, previous researches showed that increasing the expression of Aging-associated and CD4 T celldependent ectopic CXCL13 were correlated with immune-related adverse events (irAEs) incidence in ICB-treated patients [41]. FBP1, a gluconeogenesis regulatory enzyme, has been found modulate cell proliferation and chemosensitivity by targeting c-myc in breast cancer [42].…”

Section: Discussionmentioning

confidence: 99%

A novel fatty-acid metabolism-based classification for triple negative breast cancer

Xia

Tang

et al. 2023

Aging

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Background: The high heterogeneity of triple negative breast cancer (TNBC) is the main clinical challenge for individualized therapy. Considering that fatty acid metabolism (FAM) plays an indispensable role in tumorigenesis and development of TNBC, we proposed a novel FAM-based classification to characterize the tumor microenvironment immune profiles and heterogeneous for TNBC. Methods: Weighted gene correlation network analysis (WGCNA) was performed to identify FAM-related genes from 221 TNBC samples in Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset. Then, non-negative matrix factorization (NMF) clustering analysis was applied to determine FAM clusters based on the prognostic FAM-related genes, which chosen from the univariate/multivariate Cox regression model and the least absolute shrinkage and selection operator (LASSO) regression algorithm. Then, a FAM scoring scheme was constructed to further quantify FAM features of individual TNBC patient based on the prognostic differentially expressed genes (DEGs) between different FAM clusters. Systematically analyses were performed to evaluate the correlation between the FAM scoring system (FS) with survival outcomes, genomic characteristics, tumor microenvironment (TME) features and immunotherapeutic response for TNBC, which were further validated in the Cancer Genome Atlas (TCGA) and GSE58812 datasets. Moreover, the expression level and clinical significancy of the selected FS gene signatures were further validated in our cohort. Results: 1860 FAM-genes were screened out using WGCNA. Three distinct FAM clusters were determined by NMF clustering analysis, which allowed to distinguish different groups of patients with distinct clinical outcomes and tumor microenvironment (TME) features. Then, prognostic gene signatures based on the DEGs between different FAM clusters were identified using univariate Cox regression analysis and Lasso regression algorithm. A FAM scoring scheme was constructed, which could divide TNBC patients into high and low-FS subgroups. Low FS subgroup, characterized by better prognosis and abundance with effective immune infiltration. While patients with higher FS were featured with poorer survival and lack of effective immune infiltration. In addition, two independent immunotherapy cohorts (Imvigor210 and GSE78220) confirmed that patients with lower FS demonstrated significant therapeutic advantages from anti-PD-1/PD-L1 immunotherapy and durable clinical benefits. Further analyses in our cohort found that the differential expression of CXCL13, FBP1 and PLCL2 were significantly associated with clinical outcomes of TNBC samples. Conclusions: This study revealed FAM plays an indispensable role in formation of TNBC heterogeneity and TME diversity. The novel FAM-based classification could provide a promising prognostic predictor and guide more effective immunotherapy strategies for TNBC.

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Aging-associated and CD4 T-cell–dependent ectopic CXCL13 activation predisposes to anti–PD-1 therapy-induced adverse events

Cited by 25 publications

References 48 publications

Toxicity-specific peripheral blood T and B cell dynamics in anti-PD-1 and combined immune checkpoint inhibition

Toxicity-specific peripheral blood T and B cell dynamics in anti-PD-1 and combined immune checkpoint inhibition

Predictive value of CXCL10 for the occurrence of immune‐related adverse events in patient with renal cell carcinoma

A novel fatty-acid metabolism-based classification for triple negative breast cancer

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