The integrative clinical impact of tumor-infiltrating T lymphocytes and NK cells in relation to B lymphocyte and plasma cell density in esophageal and gastric adenocarcinoma

Svensson, Marcus; Warfvinge, Carl Fredrik; Fristedt, Richard; Hedner, Charlotta; Borg, David; Eberhard, Jakob; Micke, Patrick; Nodin, Björn; Leandersson, Karin; Jirström, Karin

doi:10.18632/oncotarget.19437

Cited by 51 publications

(59 citation statements)

References 40 publications

(42 reference statements)

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“…39 Indeed, CD20 + B cells within the tumor microenvironment represent important and clinically relevant markers. 40,41 However, the role of CD20 + B cells in CRC remains unclear. 42 It was suggested that a lower density of CD20 + B cell infiltration correlated with poor clinical outcomes in the primary CRC 39 A high density of CD20 + B cells was therefore significantly correlated with an improved of the overall survival of patients.…”

Section: Discussionmentioning

confidence: 99%

Local immunomodulation combined to radiofrequency ablation results in a complete cure of local and distant colorectal carcinoma

et al. 2019

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Radiofrequency ablation (RFA) of colorectal liver metastases activates a specific T-cell response that is ineffective in avoiding recurrence. Recently, local immunomodulation garnered interests as a way to improve the immune response. We were interested in improving the RFA immune response priming to propose a curative treatment of colorectal cancer (CRC) based on antitumor immunity. First, we demonstrated that the RFA did not increase the tumor infiltrating lymphocytes in secondary distant tumors of patients and in mice model and could not avoid relapse. Remarkably, RFA and in situ immunomodulation with GM-CSF-BCG hydrogel induced complete cure of microscopic secondary lesions in mice, related to a strong specific immune response. Then, we demonstrated that the immune escape of large secondary lesions was reversed by addition of the systemic PD-1 blockade to the in situ immunomodulation. The lack of an effective distant immune response in patients treated with RFA confirmed the relevance of this new combination strategy. Increasing the in situ priming response of radiofrequency ablation provides effective adjuvants to induce an abscopal effect. In the case of large lesions, synergy between PD1 blockade inhibitor, ineffective alone or after single RFA, with in situ immunomodulation, could lead to reconsideration of the use of checkpoint inhibition in metastatic MSS CRC.

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Section: Discussionmentioning

confidence: 99%

Local immunomodulation combined to radiofrequency ablation results in a complete cure of local and distant colorectal carcinoma

et al. 2019

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“…Expression levels of analyzed antigens in external cohorts of esophageal adenocarcinoma samples (TCGA n = 185) and normal esophageal mucosa samples (GTEx n = 300, ArrayExpress n = 6, TCGA n = 13 Patients with a combination of a high B and T cell infiltrate had the best prognosis, suggesting that tumor associated B and T cells synergistically inhibit tumor growth. 29 Distinct B cell subsets have been identified, which potentially promote or inhibit anti-tumor immune response. [32][33][34] The data described above highlight the prognostic relevance of B cells in solid cancer, but only very few studies analyzed the composition of B cell subsets in the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

B cells in esophago-gastric adenocarcinoma are highly differentiated, organize in tertiary lymphoid structures and produce tumor-specific antibodies

et al. 2018

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Baildon (2019) B cells in esophago-gastric adenocarcinoma are highly differentiated, organize in tertiary lymphoid structures and produce tumor-specific antibodies, OncoImmunology, 8:1, e1512458, ABSTRACT Tumor-infiltrating lymphocytes (TILs) are correlated to prognosis of several kinds of cancer. Most studies focused on T cells, while the role of tumor-associated B cells (TABs) has only recently gained more attention. TABs contain subpopulations with distinct functions, potentially promoting or inhibiting immune responses. This study provides a detailed analysis of TABs in gastro-esophageal adenocarcinoma (EAC). Flow cytometric analyses of single cell suspensions of tumor samples, mucosa, lymph nodes and peripheral blood mononuclear cells (PBMC) of EAC patients and healthy controls revealed a distinct B cell compartment in cancer patients. B cells were increased in tumor samples and subset-analyses of TILs showed increased proportions of differentiated and activated B cells and an enrichment for follicular T helper cells. Confocal microscopy demonstrated that TABs were mainly organized in tertiary lymphoid structures (TLS), which resemble lymphoid follicles in secondary lymphoid organs. A panel of 34 tumorassociated antigens (TAAs) expressed in EAC was identified based on public databases and TCGA data to analyze tumor-specific B cell responses using a LUMINEX TM bead assay and flow cytometry. Structural analyses of TLS and the detection of tumor-specific antibodies against one or more TAAs in 48.1% of analyzed serum samples underline presence of anti-tumor B cell responses in EAC. Interestingly, B cells were decreased in tumors with expression of Programmed Death Ligand 1 or impaired HLA-I expression. These data demonstrate that anti-tumor B cell responses are an additional and underestimated aspect of EAC. Our results are of immediate translational relevance to emerging immunotherapies. ARTICLE HISTORY

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“…Published data regarding the role of the immune system in the development of EACs have been conflicting [6][7][8][9]. Indeed, most studies on esophageal cancer analyze esophageal adenocarcinoma and esophageal squamous cell carcinoma together.…”

Section: Introductionmentioning

confidence: 99%

“…We focused on CD4 + T cells which orchestrate the immune system by producing a variety of different cytokines and are known to play a key role in several malignancies. Furthermore, a beneficial effect of inflammation in EACs is supported by recent studies showing that a high infiltration of CD3 + and CD8 + T cells correlates with a better prognosis [9,12,13]. However, a detailed characterization of pro-inflammatory CD4 + T cell subsets is missing.…”

Section: Introductionmentioning

confidence: 99%

“…However, the role of IL-10 in tumorigenesis and cancer progression is still controversial and its effect in EAC is unknown [17,18]. Other studies also indicate that a variety of cytokines play a role in EAC [7][8][9]13]. Kavanagh et al found elevated levels of proinflammatory cytokines IL-6, IL-1β, TNF-α and IFN-γ in addition to increased levels of anti-inflammatory IL-10 in the supernatant of EAC biopsies compared to healthy controls, indicating a mixed pro-and anti-inflammatory environment in esophageal adenocarcinomas [7].…”

Section: Introductionmentioning

confidence: 99%

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Anti-inflammatory microenvironment of esophageal adenocarcinomas negatively impacts survival

Karstens

Kempski

Giannou

et al. 2020

Cancer Immunol Immunother

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Objective Reflux promotes esophageal adenocarcinomas (EACs) creating a chronic inflammatory environment. Survival rates are low due to early local recurrences and distant metastasis. Hence, there is a need for new potential treatment options like immunotherapies. However, the inflammatory microenvironment in EACs and its impact on patient outcome remain to be fully understood. Methods mRNA expression levels of pro-and anti-inflammatory markers in 39 EAC patients without neoadjuvant radiochemotherapy were measured. Data were confirmed using flow cytometric analysis of freshly resected surgical specimens. Inflammatory alterations in premalignant lesions of Barrett's esophagus were analyzed by immunohistochemistry. Results Expression levels of IL22 were reduced in EAC, while expression levels of FOXP3, IL10 and CTLA4 were increased. Flow cytometry demonstrated a strong infiltration of CD4 + T cells with a reduction in CD4 + T cells producing IL-22 or IL-17A. We also observed an increase in CD4 + CD127 low FOXP3 + cells producing IL-10. Accumulation of FOXP3 + T cells occurred prior to malignant changes. High expression of IL10 and low expression of IL22 in EAC were associated with reduced overall survival. Moreover, increased expression of IL10, CTLA4 and PD1 in the unaltered esophageal mucosa distant to the EAC was also linked with an unfavorable prognosis. Conclusion EAC shows an anti-inflammatory environment, which strongly affects patient survival. The microscopically unaltered peritumoral tissue shows a similar anti-inflammatory pattern indicating an immunological field effect, which might contribute to early local recurrences despite radical resection. These data suggest that using checkpoint inhibitors targeting anti-inflammatory T cells would be a promising therapeutic strategy in EAC.

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The integrative clinical impact of tumor-infiltrating T lymphocytes and NK cells in relation to B lymphocyte and plasma cell density in esophageal and gastric adenocarcinoma

Cited by 51 publications

References 40 publications

Local immunomodulation combined to radiofrequency ablation results in a complete cure of local and distant colorectal carcinoma

Local immunomodulation combined to radiofrequency ablation results in a complete cure of local and distant colorectal carcinoma

B cells in esophago-gastric adenocarcinoma are highly differentiated, organize in tertiary lymphoid structures and produce tumor-specific antibodies

Anti-inflammatory microenvironment of esophageal adenocarcinomas negatively impacts survival

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