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.
Highlights
In spite of aggressive treatment with surgery, radiation, and chemotherapy, patients diagnosed with glioblastoma (GBM) have a median survival of about 15 months, and less than 10% are alive 5 years after diagnosis [1]
We found that high densities of proliferating CD8+ cells (CD8+Ki67+) and higher ratios of CD8+ Tumor infiltrating lymphocytes (TIL) relative to CD4+ TIL were associated with improved survival by multivariate analysis, in which patient age had prognostic associations
Our finding that higher ratios of CD8+ TIL relative to CD4+ TIL were associated with improved overall survival is consistent with prior studies showing enhanced survival associated with high densities of CD8+ TIL [53], low densities of CD4+ TIL [11], and increased ratios of CD8+ TIL to FoxP3+ TIL [54]
Summary
In spite of aggressive treatment with surgery, radiation, and chemotherapy, patients diagnosed with glioblastoma (GBM) have a median survival of about 15 months, and less than 10% are alive 5 years after diagnosis [1]. The presence and composition of immune cell infiltrates are prognostic in many cancers [3,4,5]. Tumor infiltrating lymphocytes (TIL) have prognostic value in a variety of cancers [3,4,5,6,7]; with a survival advantage associated with the presence of tumor infiltrating CD3+ T cells and cytotoxic CD8+ T cells [5]. The differing results may be explained in part by the use of different methods of isolation and measurement of the immune cells, the inclusion of lower grade gliomas in the analyses, and the lack of studies evaluating markers of function of TIL [15]
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