Loss of CTL Function among High-Avidity Tumor-Specific CD8+ T Cells following Tumor Infiltration

Janicki, Claire N.; Jenkinson, S. Rhiannon; Williams, Neil; Morgan, David

doi:10.1158/0008-5472.can-07-5008

Cited by 67 publications

(76 citation statements)

References 31 publications

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“…5,8,26 In recent years, functional repression in the milieu of solid tumors has been shown to also affect adoptively transferred CTLs which are preselected for strong antitumor reactivity ex vivo, thereby limiting the success of ATT. 2,3 Yet, the tumor-inflicted CTL inhibition remains poorly understood on a mechanistic level. Here we provide evidence that lactic acidosis, a common characteristic of most solid tumors, 9 is one factor that causes CTL inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…[20][21][22] However, within the milieu of a solid tumor, suppression of both IFNc secretion and degranulation associated with loss of tumor control has been observed. 2,3 It has been shown previously that exposure of CTLs to lactic acidosis milieu strongly diminished their capacity to produce cytokines. 16 We now document that the inhibitory effect of lactic acidosis on TCR-triggered cytokine production does not require preincubation but occurs immediately as soon as CTLs are placed into the lactic acidosis milieu (Fig.…”

Section: Lactic Acid Inhibits Ecd8-cell Responsesmentioning

confidence: 99%

“…Mouse models showed that adoptively transferred T cells lost their effector functions when entering the tumor environment as demonstrated by reduced degranulation and cytokine production. 2,3 Effector T cells (eCD8-cells) were able to regain activity after removal from the tumor milieu, suggesting that the milieu created by a growing tumor influences eCD8-cells in a way which makes them unable to fulfill their effector activity. 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.…”

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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

232

181

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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: Discussionmentioning

confidence: 99%

Section: Lactic Acid Inhibits Ecd8-cell Responsesmentioning

confidence: 99%

mentioning

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

232

181

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“…Inhibition of CTL function by the tumor milieu has been described in mouse models (16)(17)(18)(19). However, little information is available regarding underlying mechanisms.…”

mentioning

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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“…Low affinity TCRs do not show significant loss of function as compared to high affinity TCRs, yet low affinity tumor-antigen specific TCRs were not capable of significant anti-tumor activity. 94,95 Further, in a T cell transgenic mouse model of prostate cancer, prostate-antigen specific CD8 T cells that infiltrated the tumor microenvironment became tolerized and converted to a suppressive phenotype as measured by TGF-b production. 96 It is interesting to note that a fate of high affinity TCRs to self-antigen in thymic selection is diversion to the suppressive Treg lineage.…”

Section: Tumor Tolerance Of Tcrsmentioning

confidence: 99%

To affinity and beyond: Harnessing the T Cell receptor for cancer immunotherapy

Thaxton

2014

Human Vaccines & Immunotherapeutics

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T cell adoptive therapies for immune-mediated regression of cancers have attracted a great deal of recent attention. Clinical results are glamorous, yet much remains to be uncovered behind the basic science that allows us to engineer T cells and T cell receptors (TCRs) for clinical use. We discuss the development of TCRs for therapeutic use in the context of thymic selection toward central tolerance and we review therapies based on tumor infiltrating lymphocytes (TILs), endogenous antigen specific TCRs, and engineered TCRs. Further we discuss the development of low and high affinity TCRs and the extent to which each challenges central tolerance. Current results suggest that adaptation of TCR engineering of moderate affinity TCRs coupled with coregulatory and stimulatory molecules may be the safest and most efficacious road for TCR development aimed at tumor abolition.

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Loss of CTL Function among High-Avidity Tumor-Specific CD8+ T Cells following Tumor Infiltration

Abstract: A major problem in generating effective antitumor CTL responses is that most tumors express self-antigens to which the immune system is rendered unresponsive due to mechanisms of self-tolerance induction.

Cited by 67 publications

References 31 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

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

To affinity and beyond: Harnessing the T Cell receptor for cancer immunotherapy

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