CD8+ T Cells Induce Complete Regression of Advanced Ovarian Cancers by an Interleukin (IL)-2/IL-15–Dependent Mechanism

Yang, Taimei; Wall, Erika M.; Milne, Katy; Theiss, Patty; Watson, Peter H.; Nelson, Brad H.

doi:10.1158/1078-0432.ccr-07-1724

Cited by 18 publications

(27 citation statements)

References 58 publications

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“…Note the trend towards early improved disease-free survival for cases with rarified/clonal TCRg gene rearrangements. (Peoples et al, 1995;Goodell et al, 2008;Wiech et al, 2008) and as shown in a murine model of ovarian cancer (Yang et al, 2007). However, the correlation of Her2/neu protein expression to the presence of TILs and TCRg gene rearrangements in our group of ovarian carcinomas revealed that this is not the case, suggesting that other tumour antigens may be more promising candidate target antigens.…”

Section: Tomsovámentioning

confidence: 50%

“…This scenario has been proposed and experimentally supported in the case of HER2/neuexpressing tumour cells in breast carcinomas (Peoples et al, 1995;Wiech et al, 2008, Goodell et al, 2008. Evidence of such a mechanism for TILs in ovarian carcinoma is still sparse (Raspollini et al, 2005;Yang et al, 2007), especially as the rate of HER2/neuexpressing tumour cells varies from 1.9 to 35% (Press et al, 2005). Nevertheless, the identification of clonally restricted TILs represents an important basis for further exploitation and development of immune-based therapies (Sabbatini and Odunsi, 2007), also targeting Her2/neu (Disis et al, 2002).…”

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confidence: 92%

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Intraepithelial CD8-positive T lymphocytes predict survival for patients with serous stage III ovarian carcinomas: relevance of clonal selection of T lymphocytes

Stumpf

Hasenburg

et al. 2009

Br J Cancer

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BACKGROUND: The aim of this study was to investigate the prognostic effect of tumour-infiltrating lymphocytes (TILs) in serous stage III ovarian carcinoma to determine TIL clonality and to correlate this to Her2/neu expression. METHODS: Formalin-fixed and paraffin-embedded ovarian carcinomas were examined for CD20-, CD3-, CD4-and CD8-positive lymphocytes (n ¼ 100), and for Her2/neu-positive tumour cells (n ¼ 55/100) by immunohistochemistry. Clonality analysis was carried out by T-cell receptor g (TCRg) gene rearrangements (n ¼ 93/100). Statistical analyses included experimental and clinico-pathological variables, as well as disease-free (DFS) and overall (OS) survival. RESULTS: CD20-positive B lymphocytes were present in 57.7% (stromal)/33.0% (intraepithelial) and CD3-positive T lymphocytes in 99.0% (stromal)/90.2% (intraepithelial) of ovarian carcinomas. Intraepithelial CD3-positive T lymphocytes were correlated with improved DFS in optimally debulked patients (P ¼ 0.0402). Intraepithelial CD8-positive T lymphocytes were correlated with improved OS in all optimally debulked patients (P ¼ 0.0201) and in those undergoing paclitaxel/carboplatin therapy (P ¼ 0.0092). Finally, rarified and clonal TCRg gene rearrangements were detected in 37 out of 93 (39.8%) and 15 out of 93 (16.1%) cases, respectively. This was marginally associated with improved DFS (P ¼ 0.0873). Despite a significant correlation of HER2/neu status and intraepithelial CD8-positive lymphocytes (P ¼ 0.0264), this was non-directional (R ¼ À0.257; P ¼ 0.0626). CONCLUSION: Improved survival of ovarian cancer patients is related to the infiltration, clonal selection and intraepithelial persistence of T lymphocytes.

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Section: Tomsovámentioning

confidence: 50%

mentioning

confidence: 92%

Intraepithelial CD8-positive T lymphocytes predict survival for patients with serous stage III ovarian carcinomas: relevance of clonal selection of T lymphocytes

Stumpf

Hasenburg

et al. 2009

Br J Cancer

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“…We initially assumed that the CD11b + Gr-1 + cells accumulating in the spleen (ID8/spleen) and ascites (ID8/ascites) of the ID8-bearing mice would consist of MDSCs as previously described (20,21,29). Surprisingly, CD11b + Gr-1 + cells from both compartments did not suppress but rather enhanced both CD4 + and CD8 + T cell proliferation in vitro in both a nonspecific and an Ag-FIGURE 1.…”

Section: Cd11b + Gr-1 + Cells From Malignant Ascites Are Not Mdscsmentioning

confidence: 91%

Antigen-Specific Immunity and Cross-Priming by Epithelial Ovarian Carcinoma-Induced CD11b+Gr-1+ Cells

Tomihara

Guo

Shin

et al. 2010

The Journal of Immunology

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Both innate and adaptive immune systems are considered important for cancer prevention, immunosurveillance, and control of cancer progression. It is known that, although both systems initially eliminate emerging tumor cells efficiently, tumors eventually escape immune attack by a variety of mechanisms, including differentiation and recruitment of immunosuppressive CD11b+Gr-1+ myeloid suppressor cells into the tumor microenvironment. However, we show that CD11b+Gr-1+ cells found in ascites of epithelial ovarian cancer-bearing mice at advanced stages of disease are immunostimulatory rather than being immunosuppressive. These cells consist of a homogenous population of cells that morphologically resemble neutrophils. Moreover, like dendritic cells, immunostimulatory CD11b+Gr-1+ cells can strongly cross-prime, augmenting the proliferation of functional CTLs via signaling through the expression of costimulatory molecule CD80. Adoptive transfer of these immunostimulatory CD11b+Gr-1+ cells from ascites of ovarian cancer-bearing mice results in the significant regression of s.c. tumors even without being pulsed with exogenous tumor Ag prior to adoptive transfer. We now show for the first time that adaptive immune responses against cancer can be augmented by these cancer-induced granulocyte-like immunostimulatory myeloid (CD11b+Gr-1+) cells, thereby mediating highly effective antitumor immunity in an adoptive transfer model of immunity.

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“…In ovarian carcinoma, most studies so far have investigated their impact on overall and diseasefree survival, mainly pointing out the importance of intraepithelial CD8+ lymphocytes [17][18][19][20][21][22][23][24]. The correlation between tumor-associated lymphocytes and chemotherapy response has been the subject of only a very limited number of studies [25,26].…”

Section: Introductionmentioning

confidence: 99%

Intratumoral lymphocyte density in serous ovarian carcinoma is superior to ERCC1 expression for predicting response to platinum-based therapy

et al. 2011

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Intratumoral immune cells and ERCC1 expression are likely to play a role in the response of ovarian carcinoma to chemotherapy, but their impact on therapy outcome is still unclear. Therefore, 41 cases of optimally resected high grade serous ovarian carcinomas were examined retrospectively for stromal and intraepithelial lymphocyte populations and ERCC1 status in relation to response to platinum-based therapy. Based on RECIST criteria, 27 patients were classified as responsive and 14 as therapy resistant, respectively. Using immunohistochemistry for CD3, CD8, CD4, TIA1, MUM1 and FOX P3 on representative tumor sections, we quantitatively evaluated the intratumoral density of lymphocyte subpopulations. In addition, ERCC1 protein and mRNA expression were determined by immunohistochemistry using the Steffensen score and quantitative RT-PCR, respectively. Furthermore, ERCC1 SNP's C8092A and codon 118 were analysed. Response to chemotherapy was significantly associated with higher numbers of stromal CD3+ (mean 21.33 lymphocytes/HPF versus 8.21 lymphocytes/HPF, p = 0.002) and CD8+ lymphocytes (mean 9.22 lymphocytes/HPF versus 4.57 lymphocytes/HPF, p = 0.013). Counts of intraepithelial CD3+ and CD8+ lymphocytes, stromal and intraepithelial FOXP3+ and TIA1+ cells, CD4+ lymphocytes, and MUM1+ plasma cells did not reach statistical significance. Neither ERCC1 protein expression (p = 0.232) nor SNPs codon 118 and C8092A of the ERCC1 gene (p = 0.269 and p = 0.543) showed an association with therapy response. The same was true for ERCC1 mRNA levels (p = 0.896), probably due to intratumoral lymphocyte contamination. In conclusion, the density of CD3+ and CD8+ T-cells in tumor stroma proved to be a significant predictor for response to platinum-based therapy, whereas examination of ERCC1 failed to identify therapy-responsive patients.

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CD8+ T Cells Induce Complete Regression of Advanced Ovarian Cancers by an Interleukin (IL)-2/IL-15–Dependent Mechanism

Cited by 18 publications

References 58 publications

Intraepithelial CD8-positive T lymphocytes predict survival for patients with serous stage III ovarian carcinomas: relevance of clonal selection of T lymphocytes

Intraepithelial CD8-positive T lymphocytes predict survival for patients with serous stage III ovarian carcinomas: relevance of clonal selection of T lymphocytes

Antigen-Specific Immunity and Cross-Priming by Epithelial Ovarian Carcinoma-Induced CD11b+Gr-1+ Cells

Intratumoral lymphocyte density in serous ovarian carcinoma is superior to ERCC1 expression for predicting response to platinum-based therapy

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