Altered phenotype in peripheral blood and tumor-associated NK cells from colorectal cancer patients

Rocca, Yamila; Roberti, María Paula; Arriaga, Juan Martín; Amat, Mora; Bruno, L; Pampena, María Betina; Huertas, Eduardo; Loria, Fernando Sánchez; Pairola, Alejandro; Bianchini, Michele; Mordoh, José; Levy, Estrella Mariel

doi:10.1177/1753425912453187

Cited by 111 publications

(91 citation statements)

References 43 publications

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“…3D. We observed, as previously published in breast, lung, and colorectal cancer (12,14,17), that paired peripheral and intratumoral NK cells from the same patients displayed drastic differences in their phenotype (Supplementary Fig. S1) but our study identifies which ones are due to the tumor and not to tissue localization.…”

Section: Tumor-induced Alterations On Activating and Inhibitory Nk Cesupporting

confidence: 71%

“…Alterations of NCRs have been observed in blood from acute myeloid leukemia patients (11), and recent studies show that intratumoral NK cells display phenotypic and/or functional alterations compared with peripheral NK cells in breast cancer (12,13), lung cancer (14)(15)(16), colorectal cancer (17), renal cell carcinoma (18), and gastrointestinal stromal tumors (GIST; refs. 19,20).…”

Section: Introductionmentioning

confidence: 99%

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Inherent and Tumor-Driven Immune Tolerance in the Prostate Microenvironment Impairs Natural Killer Cell Antitumor Activity

et al. 2016

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The field of immunotherapy for solid tumors, such as prostate cancer, has been recently focusing on therapies that can counter tumor-mediated immunosuppression. Precise quantification and characterization of the immune infiltrates in tumors is crucial to improve treatment efficacy. Natural killer (NK) cells, major components of the antitumor immune system, have never been isolated from prostate tumors, despite their suspected role in disease progression. Here, we examined the frequency, phenotype, and functions of NK cells infiltrating control and tumor prostate tissues. NK cell infiltrates in prostate tissues were mainly CD56 (NCAM1)-positive and displayed an unexpected immature, but activated, phenotype with low or no cytotoxic potential. Furthermore, we show that TGFb1 (TGFB1) is highly secreted into the prostate environment and partly mediates the immunosuppressive effects on NK cells. In addition to this basal level of immunotolerance to NK cells, the prostate environment became further resistant to NK cell-mediated immunity upon cancer cell infiltration. Coculture experiments revealed that prostate cancer cells induced the expression of inhibitory receptor (ILT2/ LILRB1) and downregulated the expression of activating receptors NKp46 (NCR1), NKG2D (KLRK1), and CD16 (FCGR3) by NK cells, thus preventing their recognition of tumor cells. Notably, blood levels of NKp46 were also decreased in prostate cancer patients and were inversely correlated with levels of prostate-specific antigen, the main prognostic factor in prostate cancer. Our study shows that a strong immunosuppressive environment impairs NK cell function at multiple levels in prostate cancer and provides a rationale for the design of therapies that restore NK cell efficiency in the prostate tumor microenvironment. Cancer Res; 76(8); 2153-65. Ó2016 AACR.

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Section: Tumor-induced Alterations On Activating and Inhibitory Nk Cesupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Inherent and Tumor-Driven Immune Tolerance in the Prostate Microenvironment Impairs Natural Killer Cell Antitumor Activity

et al. 2016

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“…On the other hand, such cells are targets of NK cells since NK cells are known to kill cells expressing decreased MHC class I. Although, higher levels of circulating NK cells are associated with better prognosis 10, NK cell cytotoxic activity in peripheral blood of cancer patients is usually reduced, and the expression of NK cell activating receptors is diminished even at the early stages of cancer, as well as in advanced disease 11, 12. It is known that the cytotoxic function of NK cells is suppressed after their interaction with stem cells 13-15.…”

Section: Introductionmentioning

confidence: 99%

Differentiation by NK cells is a prerequisite for effective targeting of cancer stem cells/poorly differentiated tumors by chemopreventive and chemotherapeutic drugs

Kozłowska¹,

Topchyan²,

Kaur³

et al. 2017

J. Cancer

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Natural Killer (NK) cells target oral, pancreatic, lung, breast, glioblastoma and melanoma stem-like/poorly differentiated tumors. Differentiation of the abovementioned tumors with supernatants from split-anergized NK cells decreases their susceptibility to NK cells, but increases their sensitivity to cisplatin (CDDP)-mediated cell death. Breast and melanoma tumor cells with CD44 knockdown display enhanced susceptibility to NK cell-mediated lysis, potentially due to decreased differentiation. We also demonstrate that sulindac, a non-steroidal anti-inflammatory drug and a chemopreventive agent, not only limits the growth of oral tumor cells, but also aids in cancer cell elimination by NK cells. Treatment of oral tumors with sulindac, but not adriamycin inversely modulates the expression and function of NFκB and JNK, resulting in a significant down-regulation of IL-6, and VEGF secretion by oral tumor cells. In addition, increased secretion of IL-6 and VEGF is blocked by sulindac during interaction of oral tumors with NK cells. Sulindac treatment prevents synergistic induction of VEGF secretion by the tumor cells after their co-culture with untreated NK cells since non-activated NK cells lack the ability to efficiently kill tumor cells. Moreover, sulindac is able to profoundly reduce VEGF secretion by tumor cells cultured with IL-2 activated NK cells, which are able to significantly lyse the tumor cells. Based on the data presented in this study, we propose the following combinatorial approach for the treatment of stem-like/ poorly differentiated tumors in cancer patients with metastatic disease. Stem-like/ poorly differentiated tumor cells may in part undergo lysis or differentiation after NK cell immunotherapy, followed by treatment of differentiated tumors with chemotherapy and chemopreventive agents to eliminate the bulk of the tumor. This dual approach should limit tumor growth and prevent metastasis.

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“…When assessing cancer immunity, it is important to examine immune cells in the tumour microenvironment, which exhibit a substantial phenotypic difference from the same immune cell type in peripheral blood. [14] We speculated that immune cells in the tumour microenvironment might augment the anti-tumour effect of vitamin D, by means of their ability to enzymatically convert 25(OH)D to 1,25(OH) 2 D 3 . Therefore, we hypothesised that the lower CRC risk associated with high-level plasma vitamin D might be stronger for CRC subtype characterised by high-level immune cell infiltrates than for other CRC subtype with low-level immune cell infiltrates.…”

Section: Introductionmentioning

confidence: 99%

Plasma 25-hydroxyvitamin D and colorectal cancer risk according to tumour immunity status

Song

Nishihara

Wang

et al. 2015

Gut

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Objective Evidence suggests protective effects of vitamin D and anti-tumour immunity on colorectal cancer risk. Immune cells in tumour microenvironment can convert 25-hydroxyvitamin D [25(OH)D] to bioactive 1α,25-dihydroxyvitamin D3, which influences neoplastic and immune cells as an autocrine and paracrine factor. Thus, we hypothesised that the inverse association between vitamin D and colorectal cancer risk might be stronger for cancers with high-level immune response than those with low-level immune response. Design We designed a nested case-control study (318 rectal and colon carcinoma cases and 624 matched controls) within the Nurses’ Health Study and Health Professionals Follow-up Study, using molecular pathological epidemiology database. Multivariable conditional logistic regression was used to assess the association of plasma 25(OH)D with tumour subtypes according to the degree of lymphocytic reaction, tumour-infiltrating T-cells (CD3+, CD8+, CD45RO+ and FOXP3+ cells), microsatellite instability, or CpG island methylator phenotype. Results The association of plasma 25(OH)D with colorectal carcinoma differed by the degree of intratumoural periglandular reaction (Pheterogeneity=0.001); high 25(OH)D was associated with lower risk of tumour with high-level reaction [comparing the highest vs. lowest tertile: odds ratio, 0.10; 95% confidence interval, 0.03 to 0.35; Ptrend<0.001], but not risk of tumour with lower-level reaction (Ptrend>0.50). A statistically non-significant difference was observed for the associations of 25(OH)D with tumour subtypes according to CD3+ T-cell density (Pheterogeneity=0.03; adjusted statistical significance level of α=0.006). Conclusion High plasma 25(OH)D level is associated with lower risk of colorectal cancer with intense immune reaction, supporting a role of vitamin D in cancer immunoprevention through tumour-host interaction.

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Altered phenotype in peripheral blood and tumor-associated NK cells from colorectal cancer patients

Cited by 111 publications

References 43 publications

Inherent and Tumor-Driven Immune Tolerance in the Prostate Microenvironment Impairs Natural Killer Cell Antitumor Activity

Inherent and Tumor-Driven Immune Tolerance in the Prostate Microenvironment Impairs Natural Killer Cell Antitumor Activity

Differentiation by NK cells is a prerequisite for effective targeting of cancer stem cells/poorly differentiated tumors by chemopreventive and chemotherapeutic drugs

Plasma 25-hydroxyvitamin D and colorectal cancer risk according to tumour immunity status

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