Immunoglobulin kappa chain as an immunologic biomarker of prognosis and chemotherapy response in solid tumors

Schmidt, Marcus; Micke, Patrick; Gehrmann, Mathias; Hengstler, Jan G.

doi:10.4161/onci.21653

Cited by 31 publications

(27 citation statements)

References 23 publications

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“…A plausible explanation for this may be the different staining profiles; whereas CD138, besides plasma cells, also has reactivity in tumour cells and tumoural stroma, IGKC is exclusively expressed in plasma cells. Furthermore, IGKC has been reported as one of the top predictive genes in the B‐cell metagene, and as the most suitable marker for plasma cells in IHC studies . Further studies are warranted to compare and validate the prognostic value of IGKC and CD138 in CRC.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, IGKC has been reported as one of the top predictive genes in the B-cell metagene, and as the most suitable marker for plasma cells in IHC studies. 40 Further studies are warranted to compare and validate the prognostic value of IGKC and CD138 in CRC. CD20 expression was found to be significantly associated with KRAS wild-type tumours, which in the herein investigated cohort has been demonstrated to correlate with an improved cancer-specific survival.…”

Section: Discussionmentioning

confidence: 99%

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Prognostic impact of tumour‐infiltrating B cells and plasma cells in colorectal cancer

Berntsson

Nodin

Eberhard

et al. 2016

Intl Journal of Cancer

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220

172

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Multiple studies have described associations between infiltrating immune cells and prognosis in cancer; however, the clinical relevance has most often been attributed to the T-cell linage. This study aimed to further investigate the clinicopathological correlates and prognostic impact of B cell and plasma cell infiltration in CRC. Immunohistochemical expression of CD20, CD138 and immunoglobulin kappa C (IGKC) was analysed in tissue microarrays with tumours from 557 incident cases of CRC from a prospective population-based cohort. Kaplan-Meier analysis and Cox regression analysis were used to determine the impact of CD20, CD138 and IGKC expression on 5-year overall survival. Immune cell-specific CD20, CD138, and IGKC expression correlated significantly with lower T-stage (p < 0.001, p < 0.001, and p = 0.006, respectively). A higher density of CD20+ cells correlated significantly with an improved OS (HR = 0.53, 95% CI 0.36-0.78), remaining significant in multivariable analysis adjusted for age, TNM stage, differentiation grade and vascular invasion (HR = 0.51; 95% CI 0.33-0.80). Immune cell-specific CD138 and IGKC expression correlated significantly with an improved OS in univariable Cox regression analysis; however, these associations did not remain significant in multivariable analysis. Finally, tumour cell-specific CD138 expression was found to be an independent factor of poor prognosis (HR 1.52; 95% CI 1.03-2.24). The results from the present study demonstrate that B cell infiltration in CRC has a significant impact on tumour progression and prognosis. These findings supplement and extend the current knowledge of the immune landscape in colorectal cancer, and merit further study.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prognostic impact of tumour‐infiltrating B cells and plasma cells in colorectal cancer

Berntsson

Nodin

Eberhard

et al. 2016

Intl Journal of Cancer

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220

172

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“…For ErbB3 immunostaining in carcinomas, formalin-fixed paraffin embedded tissue was used. Breast carcinomas were available from a cohort of node-negative patients that was previously described (15,16). 200 tissues were evaluated after ErbB3 immunostaining according to the following criteria: (i) no nuclear ErbB3 staining in the entire tumor tissue; (ii) nuclear ErbB3 staining in at least 90% of all tumor cells; (iii) mixed pattern with less than 90% of the tumor cells expressing ErbB3 in the nucleus.…”

Section: Endocytosis Of Fluorescently Labeled Hrg (Hrg488)-mentioning

confidence: 99%

Activated ErbB3 Translocates to the Nucleus via Clathrin-independent Endocytosis, Which Is Associated with Proliferating Cells

Reif

Adawy

Vartak

et al. 2016

Journal of Biological Chemistry

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Members of the receptor tyrosine kinase family (RTK) have been shown to be present in the nucleus of cells; however, the mechanisms underlying their trafficking to the nucleus, and their relevance once there are poorly understood. In the present study, we focus on the RTK ErbB3 and elucidate the mechanisms regulating its trafficking. We show that heregulin-stimulation induces trafficking of phosphorylated ErbB3 from the plasma membrane to the nucleus via a clathrin-independent mechanism. Nuclear import of ErbB3 occurs via importin ␤1, which drives the receptor through the nuclear pore complex. In the nucleus, ErbB3 interacts with transcription complexes, and thereby has a role in transcriptional regulation. Our results also demonstrate that ErbB3 nuclear localization is transient as it is exported out of the nucleus by the nuclear receptor protein crm-1. Analysis of normal, regenerating tissues, and tumors showed that ErbB3 nuclear translocation is a common event in proliferating tissues.The epidermal growth factor receptor family (EGFR,3 ErbB2, ErbB3, and ErbB4) comprises some of the best characterized members of the receptor tyrosine kinases (RTKs). Their activation influences cellular signaling via the mitogen-activated protein kinase (MAPK)/ERK and the phosphatidylinositol 3-kinase (PI3K)-AKT pathways, both of which regulate essential cellular mechanisms including cell proliferation, survival, and differentiation. Dysregulation of these pathways is regularly found in carcinogenesis, tumor progression, and metastasis (1, 2). Furthermore, overexpression of EGFR, ErbB2, and ErbB3 in tumor tissue is often associated with poor patient outcome (3). ErbB3 is the least studied member of the EGFR family, However, recent evidence supports a key role for ErbB3 in cell transformation and malignancy of tumors (4). In addition, therapeutic interventions directed toward EGFR family members lead to the activation of ErbB3, which in turn is associated with the development of chemoresistance (5-8). However, the consequences of signaling activation and trafficking of ErbB3, as well as its functional relevance are poorly understood.Previous reports have shown that EGFR family members are present in the nucleus, either as full-length molecules, as in the case of EGFR (9) and ErbB2 (10), or truncated as for ␥-secretase-cleaved ErbB4 (11). In the present study, we demonstrate that nuclear translocation of ErbB3 is not limited to cancer, but appears to be a general phenomenon in proliferating tissues. To clarify ErbB3 trafficking from the cell surface to the nucleus, and its function once there, we applied a comprehensive approach using subcellular fractionation, cell surface protein labeling, immunostaining, and live cell imaging to investigate the transfer of ErbB3 to the nucleus. In addition, we studied the activation state, the translocation mechanisms, and the nuclear entry of ErbB3. To understand its function in the nucleus, we investigated the prevalence of nuclear ErbB3 in both controlled and diseased tissues. Our findings ...

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“…Another field of interest has been opened up by TIBCs strongly expressing IGKCs, in that the levels of IGKCs proved to constitute a single, robust immune biomarker predicting an improved metastasis-free survival and favorable responses to chemotherapy in patients affected by various solid tumors (see above) 64 , 89 . Due to such a reliable association with clinical endpoints, IGKC levels might therefore serve as an immunological biomarker of disease outcome in future clinical trials 90 .…”

Section: Conclusion and Clinical Perspectivesmentioning

confidence: 99%

B cell-regulated immune responses in tumor models and cancer patients

Fremd

Schuetz

Sohn³

et al. 2013

OncoImmunology

125

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The essential role played by T cells in anticancer immunity is widely accepted. The immunosuppressive functions of regulatory T cells are central for tumor progression and have been endowed with a robust predictive value. Increasing evidence indicates that also B cells have a crucial part in the regulation of T-cell responses against tumors. Although experiments reporting the production of natural antitumor antibodies and the induction of cytotoxic immune responses have revealed a tumor-protective function for B cells, other findings suggest that B cells may also exert tumor-promoting functions, resulting in a controversial picture. Here, we review recent evidence on the interactions between B and T cells in murine models and cancer patients and their implications for cancer immunology.

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Immunoglobulin kappa chain as an immunologic biomarker of prognosis and chemotherapy response in solid tumors

Cited by 31 publications

References 23 publications

Prognostic impact of tumour‐infiltrating B cells and plasma cells in colorectal cancer

Prognostic impact of tumour‐infiltrating B cells and plasma cells in colorectal cancer

Activated ErbB3 Translocates to the Nucleus via Clathrin-independent Endocytosis, Which Is Associated with Proliferating Cells

B cell-regulated immune responses in tumor models and cancer patients

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