A Transcriptionally Distinct CXCL13+CD103+CD8+ T-cell Population Is Associated with B-cell Recruitment and Neoantigen Load in Human Cancer

Workel, Hagma H.; Lubbers, Joyce M.; Arnold, Roland; Prins, Thalina M.; Vlies, Pieter van der; Lange, Katrin; Bosse, Tjalling; Gool, Inge C. van; Eggink, Florine A.; Wouters, Maartje C.A.; Komdeur, Fenne L.; Slikke, Elisabeth C. van der; Creutzberg, Carien L.; Kol, Arjan; Plat, Annechien; Glaire, Mark A.; Church, David N.; Nijman, Hans W.; Bruyn, Marco de

doi:10.1158/2326-6066.cir-18-0517

Cited by 176 publications

(147 citation statements)

References 55 publications

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“…ICOS and GITR are immune checkpoint receptors known to be co-expressed on the cell surface of exhausted T cells together with CTLA-4. 19 The relative overexpression of CTLA-4, ICOS, and GITR on regulatory T cells in our data is in line with a recent report on Treg phenotype in melanoma, non-small cell lung cancer (NSCLC), and RCC. The association of ICOS + Tregs with poor survival was previously described in ovarian cancer and more recently renal cell cancer (RCC).…”

Section: Discussionsupporting

confidence: 92%

“…To confirm the observed co-expression in CD8 + T cells, we also analyzed a recently published dataset of CD8 + TIL from ovarian cancer. 19 ICOS, TNFRSF18 (GITR), as well as in the intracellular signaling adaptor for GITR: TRAF1 were overexpressed in ICOS + vs. ICOS − TILs (Figure 4c). ICOS and GITR are also often co-expressed with immune checkpoint CTLA4 (cytotoxic T-lymphocyte attenuator 4).…”

Section: Icos and Gitr Are Co-expressed In Ovarian Cancer Patients Wimentioning

confidence: 99%

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Deep immune profiling of ovarian tumors identifies minimal MHC-I expression after neoadjuvant chemotherapy as negatively associated with T-cell-dependent outcome

Brunekreeft

Paijens

Wouters³

et al. 2020

OncoImmunology

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Epithelial Ovarian cancer (EOC) is the most lethal gynecological malignancy and has limited curative therapeutic options. Immunotherapy for EOC is promising, but clinical efficacy remains restricted to a small percentage of patients. Several lines of evidence suggest that the low response rate might be improved by combining immunotherapy with carboplatin and paclitaxel, the standard-of-care chemotherapy for EOC. Here, we assessed the immune contexture of EOC tumors, draining lymph nodes, and peripheral blood mononuclear cells during carboplatin/paclitaxel chemotherapy. We observed that the immune contexture of EOC patients is defined by the tissue of origin, independent of exposure to chemotherapy. Summarized, draining lymph nodes were characterized by a quiescent microenvironment composed of mostly non-proliferating naïve CD4 + T cells. Circulating T cells shared phenotypic features of both lymph nodes and tumor-infiltrating immune cells. Immunologically 'hot' ovarian tumors were characterized by ICOS, GITR, and PD-1 expression on CD4 + and CD8 + cells, independent of chemotherapy. The presence of PD-1 + cells in tumors prior to, but not after, chemotherapy was associated with disease-specific survival (DSS). Accordingly, we observed high MHC-I expression in tumors prior to chemotherapy, but minimal MHC-I expression in tumors after neoadjuvant chemotherapy, even though there were no differences in the number of tumor-infiltrating lymphocytes (TIL) in both groups. We therefore speculate that the TIL influx into the chemotherapy tumor microenvironment may be a consequence of the general inflammatory nature of chemotherapy-experienced tumors. Strategies to upregulate MHC-I during or after neoadjuvant chemotherapy may thus improve treatment outcome in these patients.

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Section: Discussionsupporting

confidence: 92%

Section: Icos and Gitr Are Co-expressed In Ovarian Cancer Patients Wimentioning

confidence: 99%

Deep immune profiling of ovarian tumors identifies minimal MHC-I expression after neoadjuvant chemotherapy as negatively associated with T-cell-dependent outcome

Brunekreeft

Paijens

Wouters³

et al. 2020

OncoImmunology

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“…Therefore, it is possible that at the early stage of OSCC, the local immune system may respond to antigen-stimulated immune cells, resulting in the formation of TLSs. Moreover, Workel et al 37 revealed that CXCL13 + CD103 + CD8+ TILs could also mediate B-cell recruitment and TLS formation in cancers.…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of tertiary lymphoid structure and tumour infiltrating lymphocytes in oral squamous cell carcinoma

Liu

Wang

et al. 2020

Int J Oral Sci

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Tertiary lymphoid structures (TLS) are ectopic lymphoid structures in cancers that are largely associated with favourable prognosis. However, the prognostic value of TLSs in oral squamous cell carcinoma (OSCC) is largely unknown, and the association between tumour infiltrating lymphocytes (TILs) and TLSs has been rarely explored in OSCC. In this study, associated markers of TLS, including peripheral node address (PNAd) in high endothelial venules, CD20 in B cells and CD3 in T cells, were examined in 168 OSCC patients, and survival analysis was performed between TLS-positive and TLS-negative cohorts. We detected the presence of TILs by staining CD8+ cytotoxic T cells and CD57+ NK cells as well. TLSs appeared as highly organized structures in 45 (26.8%) cases. TLS-positive patients had a better 5-year overall survival (OS) rate (88.9% vs. 56.1%, P < 0.001) and relapse-free survival (RFS) rate (88.9% vs. 63.4%, P = 0.002). Moreover, the presence of TLS was an independent prognostic factor for both the 5-year OS rate (hazard ratio [HR] = 3.784; 95% confidence interval [CI], 1.498–9.562) and RFS rate (HR = 3.296; 95% CI, 1.279–8.490) in multivariate analysis. Furthermore, a higher density of CD8+ T cells and CD57+ NK cells was found in TLS-positive sections than in TLS-negative counterparts (P < 0.001), and their combination provided a higher predictive accuracy (AUC = 0.730; 95% CI, 0.654–0.805). In conclusion, our results suggest that TLS is an independent positive prognostic factor for OSCC patients. These findings provide a theoretical basis for the future diagnostic and therapeutic value of TLSs in OSCC treatment.

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“…B cells traffic into tissue via the CXCL13-CXCR5 axis, 24 25 CXCL13 is secreted by stromal cells and follicular dendritic cells in B cell 26 and by resident memory CD8 + T cells in human cancers where CXCL13 participates in tertiary lymphoid structure formation. 27 CXCL13 is also secreted in PCa by myofibroblasts in an androgen deprivation context. 28 In contrast, CD56 (Neural Cell Adhesion Molecule, NCAM) was negatively correlated with TIS.…”

Section: Open Accessmentioning

confidence: 99%

High dose-rate brachytherapy of localized prostate cancer converts tumors from cold to hot

Keam

Halse

Nguyen

et al. 2020

J Immunother Cancer

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BackgroundProstate cancer (PCa) has a profoundly immunosuppressive microenvironment and is commonly immune excluded with few infiltrative lymphocytes and low levels of immune activation. High-dose radiation has been demonstrated to stimulate the immune system in various human solid tumors. We hypothesized that localized radiation therapy, in the form of high dose-rate brachytherapy (HDRBT), would overcome immune suppression in PCa.MethodsTo investigate whether HDRBT altered prostate immune context, we analyzed preradiation versus postradiation human tissue from a cohort of 24 patients with localized PCa that received HDRBT as primary treatment (RadBank cohort). We performed Nanostring immune gene expression profiling, digital spatial profiling, and high-throughput immune cell multiplex immunohistochemistry analysis. We also resolved tumor and nontumor zones in spatial and bioinformatic analyses to explore the immunological response.ResultsNanostring immune profiling revealed numerous immune checkpoint molecules (eg, B7-H3, CTLA4, PDL1, and PDL2) and TGFβ levels were increased in response to HDRBT. We used a published 16-gene tumor inflammation signature (TIS) to divide tumors into distinct immune activation states (high:hot, intermediate and low:cold) and showed that most localized PCa are cold tumors pre-HDRBT. Crucially, HDRBT converted 80% of these ‘cold’-phenotype tumors into an ‘intermediate’ or ‘hot’ class. We used digital spatial profiling to show these HDRBT-induced changes in prostate TIS scores were derived from the nontumor regions. Furthermore, these changes in TIS were also associated with pervasive changes in immune cell density and spatial relationships—in particular, between T cell subsets and antigen presenting cells. We identified an increased density of CD4+ FOXP3+ T cells, CD68+ macrophages and CD68+ CD11c+ dendritic cells in response to HDRBT. The only subset change specific to tumor zones was PDL1- macrophages. While these immune responses were heterogeneous, HDRBT induced significant changes in immune cell associations, including a gained T cell and HMWCK+ PDL1+ interaction in tumor zones.ConclusionIn conclusion, we showed HDRBT converted “cold” prostate tumors into more immunologically activated “hot” tissues, with accompanying spatially organized immune infiltrates and signaling changes. Understanding and potentially harnessing these changes will have widespread implications for the future treatment of localized PCa, including rational use of combination radio-immunotherapy.

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A Transcriptionally Distinct CXCL13+CD103+CD8+ T-cell Population Is Associated with B-cell Recruitment and Neoantigen Load in Human Cancer

Cited by 176 publications

References 55 publications

Deep immune profiling of ovarian tumors identifies minimal MHC-I expression after neoadjuvant chemotherapy as negatively associated with T-cell-dependent outcome

Deep immune profiling of ovarian tumors identifies minimal MHC-I expression after neoadjuvant chemotherapy as negatively associated with T-cell-dependent outcome

Prognostic value of tertiary lymphoid structure and tumour infiltrating lymphocytes in oral squamous cell carcinoma

High dose-rate brachytherapy of localized prostate cancer converts tumors from cold to hot

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