CD8+ Tumor-Infiltrating T Cells Are Deficient in Perforin-Mediated Cytolytic Activity Due to Defective Microtubule-Organizing Center Mobilization and Lytic Granule Exocytosis

Radoja, Saša; Saio, Masanao; Schaer, David; Koneru, Mythili; Vukmanović, Stanislav; Frey, Alan B.

doi:10.4049/jimmunol.167.9.5042

Cited by 143 publications

(160 citation statements)

References 43 publications

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“…Previous results from a mouse model of adenocarcinoma provided evidence that recovery of TIL lytic function requires degradation of an inhibitor that was possibly induced by some factor of the tumor microenvironment (48). IL-2 treatment may provide this opportunity, and DGK-a may be the inhibiting factor.…”

Section: Discussionmentioning

confidence: 99%

High DGK-α and Disabled MAPK Pathways Cause Dysfunction of Human Tumor-Infiltrating CD8+ T Cells That Is Reversible by Pharmacologic Intervention

Prinz

Mendler

Masouris

et al. 2012

The Journal of Immunology

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CD8+ tumor-infiltrating T cells (CD8-TILs) are found in many types of tumors including human renal cell carcinoma. However, tumor rejection rarely occurs, suggesting limited functional activity in the tumor microenvironment. In this study, we document that CD8-TILs are unresponsive to CD3 stimulation, showing neither lytic activity, nor lytic granule exocytosis, nor IFN-γ production. Mechanistically, no deficits in TCR proximal signaling molecules (lymphocyte-specific protein tyrosine kinase, phospholipase Cγ) were identified. In contrast, distal TCR signaling was suppressed, as T cells of TILs showed strongly reduced steady-state phosphorylation of the MAPK ERK and were unable to increase phosphorylation of ERK and JNK as well as AKT and AKT client proteins (IκB, GSK3) after stimulation. These deficits were tumor-specific as they were not observed in CD8+ T cells infiltrating non-tumor kidney areas (CD8+ non-tumor kidney-infiltrating lymphocytes; CD8-NILs). Diacylglycerol kinase-α (DGK-α) was more highly expressed in CD8-TILs compared with that in CD8-NILs, and its inhibition improved ERK phosphorylation and lytic granule exocytosis. Cultivation of TILs in low-dose IL-2 reduced DGK-α protein levels, increased steady-state phosphorylation of ERK, improved stimulation-induced phosphorylation of ERK and AKT, and allowed more CD8-TILs to degranulate and to produce IFN-γ. Additionally, the protein level of the AKT client molecule p27kip, an inhibitory cell cycle protein, was reduced, whereas cyclin E, which promotes G1–S phase transition, was increased. These results indicate that the tumor-inflicted deficits of TILs are reversible. DGK-α inhibition and provision of IL-2 signals could be strategies to recruit the natural CD8+ T cells to the anti-tumor response and may help prevent inactivation of adoptively transferred T cells thereby improving therapeutic efficacy.

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Section: Discussionmentioning

confidence: 99%

High DGK-α and Disabled MAPK Pathways Cause Dysfunction of Human Tumor-Infiltrating CD8+ T Cells That Is Reversible by Pharmacologic Intervention

Prinz

Mendler

Masouris

et al. 2012

The Journal of Immunology

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“…This same phenotype has been seen in CD45+ cells from ovarian tumors (Bankert et al, unpublished). The dominance of effector memory T cells in tumor microenvironments has been shown in a variety of different murine and human tumors [23][24][25], and these cells are the focus of this review. While these memory T cells can be further divided into phenotypically and functionally distinct subsets, including CD4+ cells that are distinguished by the cytokines they produce and CD8+ cytotoxic cells, they all appear to be sustained in the tumor microenvironment in a viable but hyporesponsive state.…”

Section: Inflammatory Leukocytes In the Tumor Microenvironmentmentioning

confidence: 99%

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Barnas

Simpson-Abelson

Yokota

et al. 2010

Cancer Microenvironment

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The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments.

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“…Thus, many tumors are simply ignored by the immune system because they do not function as professional APCs (1). Tolerance induction (2), incomplete "arming" (3), and impaired functional activity of tumor-infiltrating T cells (4) have also been demonstrated. Stroma surrounding cancer cells may play a critical role in preventing antitumor immunity (5).…”

Section: Lack Of Effector Cell Function and Altered Tetramer Binding mentioning

confidence: 99%

Lack of Effector Cell Function and Altered Tetramer Binding of Tumor-Infiltrating Lymphocytes

Blohm

Roth

Brommer

et al. 2002

The Journal of Immunology

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Tumor-specific CD8 T cell responses to MCA102 fibrosarcoma cells expressing the cytotoxic T cell epitope gp33 from lymphocytic choriomeningitis virus were studied. MCA102gp33 tumors grew progressively in C57BL/6 mice, despite induction of peripheral gp33-tetramer+ T cells that were capable of mediating antiviral protection, specific cell rejection, and concomitant tumor immunity. MCA102gp33 tumors were infiltrated with a high number (∼20%) of CD11b+CD11c− macrophage-phenotype cells that were able to cross-present the gp33 epitope to T cells. Tumor-infiltrating CD8 T cells exhibited a highly activated phenotype but lacked effector cell function. Strikingly, a significant portion of tumor-infiltrating lymphocytes expressed TCRs specific for gp33 but bound MHC tetramers only after cell purification and a 24-h resting period in vitro. The phenomenon of “tetramer-negative T cells” was not restricted to tumor-infiltrating lymphocytes from MCA102gp33 tumors, but was also observed when Ag-specific T cells derived from an environment with high Ag load were analyzed ex vivo. Thus, using a novel tumor model, allowing us to trace tumor-specific T cells at the single cell level in vivo, we demonstrate that the tumor microenvironment is able to alter the functional activity of T cells infiltrating the tumor mass.

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CD8+ Tumor-Infiltrating T Cells Are Deficient in Perforin-Mediated Cytolytic Activity Due to Defective Microtubule-Organizing Center Mobilization and Lytic Granule Exocytosis

Cited by 143 publications

References 43 publications

High DGK-α and Disabled MAPK Pathways Cause Dysfunction of Human Tumor-Infiltrating CD8+ T Cells That Is Reversible by Pharmacologic Intervention

High DGK-α and Disabled MAPK Pathways Cause Dysfunction of Human Tumor-Infiltrating CD8+ T Cells That Is Reversible by Pharmacologic Intervention

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Lack of Effector Cell Function and Altered Tetramer Binding of Tumor-Infiltrating Lymphocytes

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