Rescuing defective tumor-infiltrating T-cell proliferation in glioblastoma patients

Abstract

Abstract. Primary glioblastoma (GBM) is the most prevalent brain cancer, with fast progression and a poor prognosis. Current treatment options are unable to fully manage GBM since it is highly resistant to radiation and chemotherapy, and it cannot be completely removed by surgery. Thus, immunotherapeutic strategies utilizing tumor-infiltrating T cells have been investigated. In the present study, the T-cell response in GBM patients was examined in resected tumor samples and peripheral blood samples by flow cytometry. It was found that tumor-infiltrating T cells represented a rare population in all tumor cells, and were more refractory to anti-cluster of differentiation 3 (CD3) stimulation than their peripheral blood counterparts. A number of strategies were then assessed to boost tumor-infiltrating T-cell proliferation, and it was found that pre-incubation with 20 U/ml interleukin (IL)-2, as well as sequestration of IL-10 in culture, improved tumor T-cell proliferation following anti-CD3 stimulation. The stimulation of blood antigen-presenting cells by lipopolysaccharide, however, did not improve tumor T-cell proliferation. Overall, the present results provided a viable strategy for improving tumor-infiltrating CD3 + T-cell responses in GBM patients.

In-depth immunophenotyping of patients with glioblastoma multiforme: Impact of steroid treatment

“…37 In fact, T cells isolated from GBM TIL are functionally compromised and require blocking of inhibitory pathways (such as IL-10) to regain proliferative capacity in vitro. 38 GBM tumor cells themselves possess a large arsenal of immunosuppressive mechanisms, spanning from programming tumorassociated macrophages into M2 macrophages and recruiting myeloid-derived suppressor cells (MDSC) to secretion of inhibitory molecules such as TGF-b, IL-10, prostaglandins, and many others. 39 Current efforts to increase the anti-tumor immune response in GBM patients include (but are not restricted to) tumor vaccination, 40 application of checkpoint inhibitors, 41 and the targeting of unconventional lymphocytes including gd T cells.…”

Immune Microenvironment in Glioblastoma Subtypes

“…Besides TAMs, many other immune cells are also found in the GBM parenchyma, although at a much lower incidence. T cells probably account for most of the lymphoid cells in GBMs; however, they represent less than 0.25% of total tumor cells isolated from hGBM biopsy samples as examined by flow cytometry ( 25 ). CD8 + cytotoxic T cells are cellular immune effectors that are essential for killing tumor cells, but they are only sparsely distributed in the GBM parenchyma, accounting for less than a quarter of the total CD3 + T cells ( 25 ).…”

“…T cells probably account for most of the lymphoid cells in GBMs; however, they represent less than 0.25% of total tumor cells isolated from hGBM biopsy samples as examined by flow cytometry ( 25 ). CD8 + cytotoxic T cells are cellular immune effectors that are essential for killing tumor cells, but they are only sparsely distributed in the GBM parenchyma, accounting for less than a quarter of the total CD3 + T cells ( 25 ). These T cells derived from GBM patients are less responsive to direct anti-CD3 stimulation in vitro when compared to cells obtained from healthy controls, indicating an immunosuppressed status ( 25 ).…”

Brain Tumor Microenvironment and Host State: Implications for Immunotherapy

“…functions in the TME. T cells are the primary lymphoid component of the TME but compose less than 0.25% of cells isolated from human GBM biopsies (28). CD8 þ cytotoxic T lymphocytes (CTL) are considered critical for tumor clearance, but account for less than a quarter of the already sparse TIL population of the TME (28).…”

“…T cells are the primary lymphoid component of the TME but compose less than 0.25% of cells isolated from human GBM biopsies (28). CD8 þ cytotoxic T lymphocytes (CTL) are considered critical for tumor clearance, but account for less than a quarter of the already sparse TIL population of the TME (28). Functional characterization of the CTLs found in the TME has shown that these cells have impaired effector functions and an exhausted phenotype, rendering them ineffective in their role as cytotoxic lymphocytes (29).…”