Proliferating CD8<sup<+</sup< T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma

Background: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. Methods: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. Results: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.36, <i<p</i< = 0.001) and CD20<sup<+</sup< cells (HR 0.51, <i<p</i< = 0.008), as well as CD8<sup<+</sup<Tbet<sup<+</sup< cells (HR 0.46, <i<p</i< = 0.004), and RORγt<sup<+</sup< cells (HR 0.56, <i<p</i< = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, <i<p</i< = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.15, <i<p</i< < 0.001), and higher ratios of CD8<sup<+</sup< cells to CD4<sup<+</sup< cells (HR 0.31, <i<p</i< = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, <i<p</i< = 0.005) and higher mean intensities of IFNγ (HR 2.13, <i<p</i< = 0.027). Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8<sup<+</sup< T cells and that approaches may be needed to promote CD8<sup<+</sup< T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Ileana S. Mauldin [verfasserIn] Jasmin Jo [verfasserIn] Nolan A. Wages [verfasserIn] Lalanthica V. Yogendran [verfasserIn] Adela Mahmutovic [verfasserIn] Samuel J. Young [verfasserIn] Maria Beatriz Lopes [verfasserIn] Craig L. Slingluff [verfasserIn] Loren D. Erickson [verfasserIn] Camilo E. Fadul [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Schlagwörter:	immunology tumor infiltrating lymphocytes multiplex immunofluorescence histology glioblastoma human

Übergeordnetes Werk:	In: Cells - MDPI AG, 2012, 10(2021), 12, p 3378
Übergeordnetes Werk:	volume:10 ; year:2021 ; number:12, p 3378

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/cells10123378

Katalog-ID:	DOAJ07431145X

Internformat


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100	0		\|a Ileana S. Mauldin \|e verfasserin \|4 aut
245	1	0	\|a Proliferating CD8<sup<+</sup< T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma
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520			\|a Background: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. Methods: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. Results: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.36, <i<p</i< = 0.001) and CD20<sup<+</sup< cells (HR 0.51, <i<p</i< = 0.008), as well as CD8<sup<+</sup<Tbet<sup<+</sup< cells (HR 0.46, <i<p</i< = 0.004), and RORγt<sup<+</sup< cells (HR 0.56, <i<p</i< = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, <i<p</i< = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.15, <i<p</i< < 0.001), and higher ratios of CD8<sup<+</sup< cells to CD4<sup<+</sup< cells (HR 0.31, <i<p</i< = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, <i<p</i< = 0.005) and higher mean intensities of IFNγ (HR 2.13, <i<p</i< = 0.027). Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8<sup<+</sup< T cells and that approaches may be needed to promote CD8<sup<+</sup< T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment.
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700	0		\|a Camilo E. Fadul \|e verfasserin \|4 aut
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author_variant	i s m ism j j jj n a w naw l v y lvy a m am s j y sjy m b l mbl c l s cls l d e lde c e f cef
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allfields	10.3390/cells10123378 doi (DE-627)DOAJ07431145X (DE-599)DOAJd8a074cdd63a4a6ea6817f1f57968905 DE-627 ger DE-627 rakwb eng QH573-671 Ileana S. Mauldin verfasserin aut Proliferating CD8<sup<+</sup< T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. Methods: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. Results: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.36, <i<p</i< = 0.001) and CD20<sup<+</sup< cells (HR 0.51, <i<p</i< = 0.008), as well as CD8<sup<+</sup<Tbet<sup<+</sup< cells (HR 0.46, <i<p</i< = 0.004), and RORγt<sup<+</sup< cells (HR 0.56, <i<p</i< = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, <i<p</i< = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.15, <i<p</i< < 0.001), and higher ratios of CD8<sup<+</sup< cells to CD4<sup<+</sup< cells (HR 0.31, <i<p</i< = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, <i<p</i< = 0.005) and higher mean intensities of IFNγ (HR 2.13, <i<p</i< = 0.027). Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8<sup<+</sup< T cells and that approaches may be needed to promote CD8<sup<+</sup< T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment. immunology tumor infiltrating lymphocytes multiplex immunofluorescence histology glioblastoma human Cytology Jasmin Jo verfasserin aut Nolan A. Wages verfasserin aut Lalanthica V. Yogendran verfasserin aut Adela Mahmutovic verfasserin aut Samuel J. Young verfasserin aut Maria Beatriz Lopes verfasserin aut Craig L. Slingluff verfasserin aut Loren D. Erickson verfasserin aut Camilo E. Fadul verfasserin aut In Cells MDPI AG, 2012 10(2021), 12, p 3378 (DE-627)718622081 (DE-600)2661518-6 20734409 nnns volume:10 year:2021 number:12, p 3378 https://doi.org/10.3390/cells10123378 kostenfrei https://doaj.org/article/d8a074cdd63a4a6ea6817f1f57968905 kostenfrei https://www.mdpi.com/2073-4409/10/12/3378 kostenfrei https://doaj.org/toc/2073-4409 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2021 12, p 3378
spelling	10.3390/cells10123378 doi (DE-627)DOAJ07431145X (DE-599)DOAJd8a074cdd63a4a6ea6817f1f57968905 DE-627 ger DE-627 rakwb eng QH573-671 Ileana S. Mauldin verfasserin aut Proliferating CD8<sup<+</sup< T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. Methods: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. Results: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.36, <i<p</i< = 0.001) and CD20<sup<+</sup< cells (HR 0.51, <i<p</i< = 0.008), as well as CD8<sup<+</sup<Tbet<sup<+</sup< cells (HR 0.46, <i<p</i< = 0.004), and RORγt<sup<+</sup< cells (HR 0.56, <i<p</i< = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, <i<p</i< = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.15, <i<p</i< < 0.001), and higher ratios of CD8<sup<+</sup< cells to CD4<sup<+</sup< cells (HR 0.31, <i<p</i< = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, <i<p</i< = 0.005) and higher mean intensities of IFNγ (HR 2.13, <i<p</i< = 0.027). Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8<sup<+</sup< T cells and that approaches may be needed to promote CD8<sup<+</sup< T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment. immunology tumor infiltrating lymphocytes multiplex immunofluorescence histology glioblastoma human Cytology Jasmin Jo verfasserin aut Nolan A. Wages verfasserin aut Lalanthica V. Yogendran verfasserin aut Adela Mahmutovic verfasserin aut Samuel J. Young verfasserin aut Maria Beatriz Lopes verfasserin aut Craig L. Slingluff verfasserin aut Loren D. Erickson verfasserin aut Camilo E. Fadul verfasserin aut In Cells MDPI AG, 2012 10(2021), 12, p 3378 (DE-627)718622081 (DE-600)2661518-6 20734409 nnns volume:10 year:2021 number:12, p 3378 https://doi.org/10.3390/cells10123378 kostenfrei https://doaj.org/article/d8a074cdd63a4a6ea6817f1f57968905 kostenfrei https://www.mdpi.com/2073-4409/10/12/3378 kostenfrei https://doaj.org/toc/2073-4409 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2021 12, p 3378
allfields_unstemmed	10.3390/cells10123378 doi (DE-627)DOAJ07431145X (DE-599)DOAJd8a074cdd63a4a6ea6817f1f57968905 DE-627 ger DE-627 rakwb eng QH573-671 Ileana S. Mauldin verfasserin aut Proliferating CD8<sup<+</sup< T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. Methods: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. Results: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.36, <i<p</i< = 0.001) and CD20<sup<+</sup< cells (HR 0.51, <i<p</i< = 0.008), as well as CD8<sup<+</sup<Tbet<sup<+</sup< cells (HR 0.46, <i<p</i< = 0.004), and RORγt<sup<+</sup< cells (HR 0.56, <i<p</i< = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, <i<p</i< = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.15, <i<p</i< < 0.001), and higher ratios of CD8<sup<+</sup< cells to CD4<sup<+</sup< cells (HR 0.31, <i<p</i< = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, <i<p</i< = 0.005) and higher mean intensities of IFNγ (HR 2.13, <i<p</i< = 0.027). Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8<sup<+</sup< T cells and that approaches may be needed to promote CD8<sup<+</sup< T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment. immunology tumor infiltrating lymphocytes multiplex immunofluorescence histology glioblastoma human Cytology Jasmin Jo verfasserin aut Nolan A. Wages verfasserin aut Lalanthica V. Yogendran verfasserin aut Adela Mahmutovic verfasserin aut Samuel J. Young verfasserin aut Maria Beatriz Lopes verfasserin aut Craig L. Slingluff verfasserin aut Loren D. Erickson verfasserin aut Camilo E. Fadul verfasserin aut In Cells MDPI AG, 2012 10(2021), 12, p 3378 (DE-627)718622081 (DE-600)2661518-6 20734409 nnns volume:10 year:2021 number:12, p 3378 https://doi.org/10.3390/cells10123378 kostenfrei https://doaj.org/article/d8a074cdd63a4a6ea6817f1f57968905 kostenfrei https://www.mdpi.com/2073-4409/10/12/3378 kostenfrei https://doaj.org/toc/2073-4409 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2021 12, p 3378
allfieldsGer	10.3390/cells10123378 doi (DE-627)DOAJ07431145X (DE-599)DOAJd8a074cdd63a4a6ea6817f1f57968905 DE-627 ger DE-627 rakwb eng QH573-671 Ileana S. Mauldin verfasserin aut Proliferating CD8<sup<+</sup< T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. Methods: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. Results: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.36, <i<p</i< = 0.001) and CD20<sup<+</sup< cells (HR 0.51, <i<p</i< = 0.008), as well as CD8<sup<+</sup<Tbet<sup<+</sup< cells (HR 0.46, <i<p</i< = 0.004), and RORγt<sup<+</sup< cells (HR 0.56, <i<p</i< = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, <i<p</i< = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.15, <i<p</i< < 0.001), and higher ratios of CD8<sup<+</sup< cells to CD4<sup<+</sup< cells (HR 0.31, <i<p</i< = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, <i<p</i< = 0.005) and higher mean intensities of IFNγ (HR 2.13, <i<p</i< = 0.027). Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8<sup<+</sup< T cells and that approaches may be needed to promote CD8<sup<+</sup< T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment. immunology tumor infiltrating lymphocytes multiplex immunofluorescence histology glioblastoma human Cytology Jasmin Jo verfasserin aut Nolan A. Wages verfasserin aut Lalanthica V. Yogendran verfasserin aut Adela Mahmutovic verfasserin aut Samuel J. Young verfasserin aut Maria Beatriz Lopes verfasserin aut Craig L. Slingluff verfasserin aut Loren D. Erickson verfasserin aut Camilo E. Fadul verfasserin aut In Cells MDPI AG, 2012 10(2021), 12, p 3378 (DE-627)718622081 (DE-600)2661518-6 20734409 nnns volume:10 year:2021 number:12, p 3378 https://doi.org/10.3390/cells10123378 kostenfrei https://doaj.org/article/d8a074cdd63a4a6ea6817f1f57968905 kostenfrei https://www.mdpi.com/2073-4409/10/12/3378 kostenfrei https://doaj.org/toc/2073-4409 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2021 12, p 3378
allfieldsSound	10.3390/cells10123378 doi (DE-627)DOAJ07431145X (DE-599)DOAJd8a074cdd63a4a6ea6817f1f57968905 DE-627 ger DE-627 rakwb eng QH573-671 Ileana S. Mauldin verfasserin aut Proliferating CD8<sup<+</sup< T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. Methods: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. Results: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.36, <i<p</i< = 0.001) and CD20<sup<+</sup< cells (HR 0.51, <i<p</i< = 0.008), as well as CD8<sup<+</sup<Tbet<sup<+</sup< cells (HR 0.46, <i<p</i< = 0.004), and RORγt<sup<+</sup< cells (HR 0.56, <i<p</i< = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, <i<p</i< = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.15, <i<p</i< < 0.001), and higher ratios of CD8<sup<+</sup< cells to CD4<sup<+</sup< cells (HR 0.31, <i<p</i< = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, <i<p</i< = 0.005) and higher mean intensities of IFNγ (HR 2.13, <i<p</i< = 0.027). Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8<sup<+</sup< T cells and that approaches may be needed to promote CD8<sup<+</sup< T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment. immunology tumor infiltrating lymphocytes multiplex immunofluorescence histology glioblastoma human Cytology Jasmin Jo verfasserin aut Nolan A. Wages verfasserin aut Lalanthica V. Yogendran verfasserin aut Adela Mahmutovic verfasserin aut Samuel J. Young verfasserin aut Maria Beatriz Lopes verfasserin aut Craig L. Slingluff verfasserin aut Loren D. Erickson verfasserin aut Camilo E. Fadul verfasserin aut In Cells MDPI AG, 2012 10(2021), 12, p 3378 (DE-627)718622081 (DE-600)2661518-6 20734409 nnns volume:10 year:2021 number:12, p 3378 https://doi.org/10.3390/cells10123378 kostenfrei https://doaj.org/article/d8a074cdd63a4a6ea6817f1f57968905 kostenfrei https://www.mdpi.com/2073-4409/10/12/3378 kostenfrei https://doaj.org/toc/2073-4409 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2021 12, p 3378
language	English
source	In Cells 10(2021), 12, p 3378 volume:10 year:2021 number:12, p 3378
sourceStr	In Cells 10(2021), 12, p 3378 volume:10 year:2021 number:12, p 3378
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	immunology tumor infiltrating lymphocytes multiplex immunofluorescence histology glioblastoma human Cytology
isfreeaccess_bool	true
container_title	Cells
authorswithroles_txt_mv	Ileana S. Mauldin @@aut@@ Jasmin Jo @@aut@@ Nolan A. Wages @@aut@@ Lalanthica V. Yogendran @@aut@@ Adela Mahmutovic @@aut@@ Samuel J. Young @@aut@@ Maria Beatriz Lopes @@aut@@ Craig L. Slingluff @@aut@@ Loren D. Erickson @@aut@@ Camilo E. Fadul @@aut@@
publishDateDaySort_date	2021-01-01T00:00:00Z
hierarchy_top_id	718622081
id	DOAJ07431145X
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">DOAJ07431145X</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20240412095156.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230228s2021 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.3390/cells10123378</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ07431145X</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJd8a074cdd63a4a6ea6817f1f57968905</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">QH573-671</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Ileana S. Mauldin</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Proliferating CD8<sup<+</sup< T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2021</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Background: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. Methods: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. Results: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.36, <i<p</i< = 0.001) and CD20<sup<+</sup< cells (HR 0.51, <i<p</i< = 0.008), as well as CD8<sup<+</sup<Tbet<sup<+</sup< cells (HR 0.46, <i<p</i< = 0.004), and RORγt<sup<+</sup< cells (HR 0.56, <i<p</i< = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, <i<p</i< = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.15, <i<p</i< < 0.001), and higher ratios of CD8<sup<+</sup< cells to CD4<sup<+</sup< cells (HR 0.31, <i<p</i< = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, <i<p</i< = 0.005) and higher mean intensities of IFNγ (HR 2.13, <i<p</i< = 0.027). Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8<sup<+</sup< T cells and that approaches may be needed to promote CD8<sup<+</sup< T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">immunology</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">tumor infiltrating lymphocytes</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">multiplex immunofluorescence histology</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">glioblastoma</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">human</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Cytology</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Jasmin Jo</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Nolan A. 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callnumber-first	Q - Science
author	Ileana S. Mauldin
spellingShingle	Ileana S. Mauldin misc QH573-671 misc immunology misc tumor infiltrating lymphocytes misc multiplex immunofluorescence histology misc glioblastoma misc human misc Cytology Proliferating CD8<sup<+</sup< T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma
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topic_title	QH573-671 Proliferating CD8<sup<+</sup< T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma immunology tumor infiltrating lymphocytes multiplex immunofluorescence histology glioblastoma human
topic	misc QH573-671 misc immunology misc tumor infiltrating lymphocytes misc multiplex immunofluorescence histology misc glioblastoma misc human misc Cytology
topic_unstemmed	misc QH573-671 misc immunology misc tumor infiltrating lymphocytes misc multiplex immunofluorescence histology misc glioblastoma misc human misc Cytology
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title	Proliferating CD8<sup<+</sup< T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma
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title_full	Proliferating CD8<sup<+</sup< T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma
author_sort	Ileana S. Mauldin
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author_browse	Ileana S. Mauldin Jasmin Jo Nolan A. Wages Lalanthica V. Yogendran Adela Mahmutovic Samuel J. Young Maria Beatriz Lopes Craig L. Slingluff Loren D. Erickson Camilo E. Fadul
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title_sort	proliferating cd8<sup<+</sup< t cell infiltrates are associated with improved survival in glioblastoma
callnumber	QH573-671
title_auth	Proliferating CD8<sup<+</sup< T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma
abstract	Background: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. Methods: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. Results: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.36, <i<p</i< = 0.001) and CD20<sup<+</sup< cells (HR 0.51, <i<p</i< = 0.008), as well as CD8<sup<+</sup<Tbet<sup<+</sup< cells (HR 0.46, <i<p</i< = 0.004), and RORγt<sup<+</sup< cells (HR 0.56, <i<p</i< = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, <i<p</i< = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.15, <i<p</i< < 0.001), and higher ratios of CD8<sup<+</sup< cells to CD4<sup<+</sup< cells (HR 0.31, <i<p</i< = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, <i<p</i< = 0.005) and higher mean intensities of IFNγ (HR 2.13, <i<p</i< = 0.027). Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8<sup<+</sup< T cells and that approaches may be needed to promote CD8<sup<+</sup< T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment.
abstractGer	Background: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. Methods: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. Results: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.36, <i<p</i< = 0.001) and CD20<sup<+</sup< cells (HR 0.51, <i<p</i< = 0.008), as well as CD8<sup<+</sup<Tbet<sup<+</sup< cells (HR 0.46, <i<p</i< = 0.004), and RORγt<sup<+</sup< cells (HR 0.56, <i<p</i< = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, <i<p</i< = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.15, <i<p</i< < 0.001), and higher ratios of CD8<sup<+</sup< cells to CD4<sup<+</sup< cells (HR 0.31, <i<p</i< = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, <i<p</i< = 0.005) and higher mean intensities of IFNγ (HR 2.13, <i<p</i< = 0.027). Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8<sup<+</sup< T cells and that approaches may be needed to promote CD8<sup<+</sup< T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment.
abstract_unstemmed	Background: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. Methods: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. Results: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.36, <i<p</i< = 0.001) and CD20<sup<+</sup< cells (HR 0.51, <i<p</i< = 0.008), as well as CD8<sup<+</sup<Tbet<sup<+</sup< cells (HR 0.46, <i<p</i< = 0.004), and RORγt<sup<+</sup< cells (HR 0.56, <i<p</i< = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, <i<p</i< = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67<sup<+</sup<) CD8<sup<+</sup< cells (HR 0.15, <i<p</i< < 0.001), and higher ratios of CD8<sup<+</sup< cells to CD4<sup<+</sup< cells (HR 0.31, <i<p</i< = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, <i<p</i< = 0.005) and higher mean intensities of IFNγ (HR 2.13, <i<p</i< = 0.027). Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8<sup<+</sup< T cells and that approaches may be needed to promote CD8<sup<+</sup< T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment.
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title_short	Proliferating CD8<sup<+</sup< T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma
url	https://doi.org/10.3390/cells10123378 https://doaj.org/article/d8a074cdd63a4a6ea6817f1f57968905 https://www.mdpi.com/2073-4409/10/12/3378 https://doaj.org/toc/2073-4409
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Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. 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Proliferating CD8<sup<+</sup< T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma

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