Immune suppression in renal cell carcinoma

Frankenberger, Bernhard; Noeßner, Elfriede; Schendel, Dolores J.

doi:10.1016/j.semcancer.2007.06.004

Cited by 33 publications

(42 citation statements)

References 112 publications

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“…This could be the result of other inhibitory factors, in addition to lactic acid, present in the TS. [5][6][7] As seen for 20 mM lactic acid, CTL stimulation within TS hi showed reduced phosphorylation of p38, JNK and c-Jun, but not ERK or ZAP70 (Figs. 5b and 5c).…”

Section: Recovery Of Ecd8 Function After Removal From the Lactic Milieumentioning

confidence: 56%

“…4,5 Inhibition of eCD8-cells by the tumor milieu can be caused by (i) upregulation of inhibitory receptors like programmed death 1 (PD1) on the effector cells, (ii) cells within the tumor, like regulatory T cells or myeloid-derived suppressor cells (MDSCs) or (iii) soluble factors, such as cytokines (TGF-b, IL10), indoleamine 2,3-dioxygenase (IDO), arginase, nucleotides or metabolites produced by the tumor cells. [5][6][7] Of the latter, high lactate and extracellular acidosis are common characteristics of solid tumors. 8,9 Accumulation of lactic acid in solid tumors is a byproduct of hypoxia as tumors are forced to switch to an anaerobe energy production.…”

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confidence: 99%

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Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c‐Jun activation

Mendler

Prinz

et al. 2011

Intl Journal of Cancer

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Lactic acidosis is common to most solid tumors and has been found to affect infiltrating immune cells. Here we document effector phase inhibition of cytotoxic T cells (CTLs) involving complete blockage of cytokine production and partial impairment of lytic granule exocytosis. Lactic acidosis impaired TCR‐triggered phosphorylation of JNK, c‐Jun and p38, while not affecting MEK1 and ERK. The select targeting of signaling proteins involved in IFNγ production (JNK/c‐Jun, p38) without affecting those jointly used in cytokine regulation and granule exocytosis (MEK1/ERK) explains the observed split effect of lactic acidosis on the CTL responses. CTL inhibition by lactic acidosis showed fast dynamics with immediate onset and reversion. Functional recovery by neutralizing the extracellular pH despite continuous presence of lactate holds promise that CTL activity can be improved in the milieu of solid tumors with appropriate anti‐acidosis treatment, thereby increasing the efficacy of adoptive T cell therapy.

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Section: Recovery Of Ecd8 Function After Removal From the Lactic Milieumentioning

confidence: 56%

mentioning

confidence: 99%

Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c‐Jun activation

Mendler

Prinz

et al. 2011

Intl Journal of Cancer

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242

181

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“…This could be explained by preexisting tumor-induced immunosuppression, as has Gene-modified tumor cell vaccine in metastatic RCC J Westermann et al been previously described in RCC. 23 Immunosuppression might be caused by high tumor burden and may explain the inability of the vaccine to induce efficient anti-tumor immunity. Alternatively, the insufficient anti-tumor immune response could be attributable to the vaccine itself, such that a lack of immunogenicity is inherent to RCC26/IL-7/CD80 cells.…”

Section: Discussionmentioning

confidence: 99%

Allogeneic gene-modified tumor cells (RCC-26/IL-7/CD80) as a vaccine in patients with metastatic renal cell cancer: a clinical phase-I study

et al. 2010

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Despite novel targeted agents, prognosis of metastatic renal cell cancer (RCC) remains poor, and experimental therapeutic strategies are warranted. Transfection of tumor cells with co-stimulatory molecules and/or cytokines is able to increase immunogenicity. Therefore, in our clinical study, 10 human leukocyte antigen (HLA)-A*0201 + patients with histologicallyconfirmed progressive metastatic clear cell RCC were immunized repetitively over 22 weeks with 2.5-40Â10 6 interleukin (IL)-7/CD80 cotransfected allogeneic HLA-A*0201 + tumor cells (RCC26/IL-7/CD80). Endpoints of the study were feasibility, safety, immunological and clinical responses. Vaccination was feasible and safe. In all, 50% of the patients showed stable disease throughout the study; the median time to progression was 18 weeks. However, vaccination with allogeneic RCC26/IL-7/ CD80 tumor cells was not able to induce TH1-polarized immune responses. A TH2 cytokine profile with increasing amounts of antigen-specific IL-10 secretion was observed in most of the responding patients. Interferon-g secretion by patient lymphocytes upon antigen-specific and non-specific stimulation was substantially impaired, both before and during vaccination, as compared with healthy controls. This is possibly due to profound tumor-induced immunosuppression, which may prevent induction of antitumor immune responses by the gene-modified vaccine. Vaccination in minimal residual disease with concurrent depletion of regulatory cells might be one strategy to overcome this limitation.

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“…Various evasion mechanisms have been acknowledged ranging from ignorance to active suppression (8)(9)(10). The most common ones observed in many tumors, such as lack of infiltration with cytotoxic lymphocytes or loss of MHC class I, do not explain the immune escape of human RCC satisfactorily: RCC tissues are generally strongly infiltrated by various types of immune cells that are considered to be associated with an effective immune response, notably dendritic cells, NK cells, and CD8 + T lymphocytes expressing MHC class I-restricted tumor-reactive TCRs (5-7, 11, 12).…”

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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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Immune suppression in renal cell carcinoma

Cited by 33 publications

References 112 publications

Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c‐Jun activation

Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c‐Jun activation

Allogeneic gene-modified tumor cells (RCC-26/IL-7/CD80) as a vaccine in patients with metastatic renal cell cancer: a clinical phase-I study

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

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