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

Ileana S Mauldin, Jasmin Jo, Nolan A Wages, Lalanthica V Yogendran, Adela Mahmutovic, Samuel J Young, Maria Beatriz Lopes, Craig L Slingluff Jr, Loren D Erickson, Camilo E Fadul, Ileana S Mauldin, Jasmin Jo, Nolan A Wages, Lalanthica V Yogendran, Adela Mahmutovic, Samuel J Young, Maria Beatriz Lopes, Craig L Slingluff Jr, Loren D Erickson, Camilo E Fadul

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+) CD8+ cells (HR 0.36, p = 0.001) and CD20+ cells (HR 0.51, p = 0.008), as well as CD8+Tbet+ cells (HR 0.46, p = 0.004), and RORγt+ cells (HR 0.56, p = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, p = 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+) CD8+ cells (HR 0.15, p < 0.001), and higher ratios of CD8+ cells to CD4+ cells (HR 0.31, p = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, p = 0.005) and higher mean intensities of IFNγ (HR 2.13, p = 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+ T cells and that approaches may be needed to promote CD8+ T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment.

Keywords: glioblastoma; human; immunology; multiplex immunofluorescence histology; tumor infiltrating lymphocytes.

Conflict of interest statement

Craig L. Slingluff, Jr. has the following disclosures, none of which conflict with the present manuscript: research support to the University of Virginia from Celldex (funding, drug), GlaxoSmithKline (funding), Merck (funding, drug), 3M (drug), Theraclion (device staff support); Funding to the University of Virginia from Polynoma for PI role on the MAVIS Clinical Trial; funding to the University of Virginia for roles on Scientific Advisory Boards for Immatics and CureVac. Moreover, Craig L. Slingluff, Jr. receives licensing fee payments through the UVA Licensing and Ventures Group for patents for peptides used in cancer vaccines. The other authors do not have any financial conflicts to disclose that are relevant to this manuscript.

Figures

Figure 1
Figure 1
Images of TIL in GBM and immune cell densities. (A) Representative 5 color mIFH image of T (CD4+ and CD8+) and B cells (CD20+) localized near CD34+ endothelial cells in GBM. Colored arrows denote one example of each cell type in image. (B) Box plots of the densities of immune cell subsets per mm2 tissue within GBM. The central box represents values from the lower to upper quartile, 25th to 75th percentile. Middle bar identifies median, and whiskers show minimum and maximum, outliers are displayed as separate points. (C–E) Images of proliferating CD8+ T cells in GBM. Image C is a 3 color mIFH image showing CD8+ T cells and proliferating Ki67+ cells, Image D depicts CD8+ cells, and image E is of Ki67+ cells, white arrows in each image point to proliferating CD8+Ki67+ cells. (F,G) Image of T-bet+ T cells in GBM. Image F is a 4 color mIFH image depicting CD8+ or CD4+ T cells and T-bet nuclear staining, image G shows T-bet expression alone, green arrows denote CD8+T-bet+ cells and cyan arrows denote CD4+T-bet+ cells. (H) Image of RORγt+ cells in GBM, nuclear staining of RORγt+ is shown in red, and is denoted by red arrows. (I) Representative Image of IFNγt+ cells in GBM. Image I is a 4 color mIFH image depicting CD4+ or CD8+ T cells and IFNγ expression in GBM. For all images colors are indicated, scale bars are 100 μm and DAPI nuclear staining is shown in Blue. (J) Box plot of the average cell intensities of IFNγin GBM.
Figure 1
Figure 1
Images of TIL in GBM and immune cell densities. (A) Representative 5 color mIFH image of T (CD4+ and CD8+) and B cells (CD20+) localized near CD34+ endothelial cells in GBM. Colored arrows denote one example of each cell type in image. (B) Box plots of the densities of immune cell subsets per mm2 tissue within GBM. The central box represents values from the lower to upper quartile, 25th to 75th percentile. Middle bar identifies median, and whiskers show minimum and maximum, outliers are displayed as separate points. (C–E) Images of proliferating CD8+ T cells in GBM. Image C is a 3 color mIFH image showing CD8+ T cells and proliferating Ki67+ cells, Image D depicts CD8+ cells, and image E is of Ki67+ cells, white arrows in each image point to proliferating CD8+Ki67+ cells. (F,G) Image of T-bet+ T cells in GBM. Image F is a 4 color mIFH image depicting CD8+ or CD4+ T cells and T-bet nuclear staining, image G shows T-bet expression alone, green arrows denote CD8+T-bet+ cells and cyan arrows denote CD4+T-bet+ cells. (H) Image of RORγt+ cells in GBM, nuclear staining of RORγt+ is shown in red, and is denoted by red arrows. (I) Representative Image of IFNγt+ cells in GBM. Image I is a 4 color mIFH image depicting CD4+ or CD8+ T cells and IFNγ expression in GBM. For all images colors are indicated, scale bars are 100 μm and DAPI nuclear staining is shown in Blue. (J) Box plot of the average cell intensities of IFNγin GBM.
Figure 2
Figure 2
GBM contain focal B and T cell aggregates resembling immature TLS. (A,B) Representative images of dense clusters of CD20+ B cells, CD8+ T cells, and PNAd+ vasculature from two GBM specimens. The circles denote RORγt+ cells, scale bars are 100 μm and colors are indicated.
Figure 3
Figure 3
Markers of immune activity are associated with OS in GBM. Kaplan–Meier curves for the indicated immune markers, dichotomized into high (blue) and low (yellow), are shown in (A–E). Prolonged OS is associated with tumors containing high densities of: CD8+Ki67+ cell infiltrates high (22.8 months) vs. low (7.7 months) (A); CD20+Ki67+ cell infiltrates high (22.8 months) vs. low (12.4 months) (B); CD8+Tbet+ cell infiltrates high (20.5 months) vs. low (10.6 months) (C); and RORγt+ cell infiltrates high (18.7 months) vs. low (10.5 months) (D). Diminished OS was associated with tumors expressing higher mean intensities of IFNγ (30.9 months) vs. low (14.2 months) (E).

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Source: PubMed

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