Cancer-Induced Signaling Defects in Antitumor T Cells

Frey, Alan B.

doi:10.1007/978-0-387-69118-3_5

Cited by 7 publications

(8 citation statements)

References 146 publications

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“…Absent TCRζ (and/or p56 lck ) has been suggested to be responsible for various phenotypes in anti‐tumor T cells (and also in PBL T cells in patients) including the following: decreased proliferation, decreased cytokine secretion, defective lytic function, and, counter intuitively, enhanced apoptosis. This specific candidate basis of suppression of the anti‐tumor immune response has been recently reviewed in detail (91), and we conclude that the evidence in support for a role of decreased TCRζ in T cells of cancer‐bearing patients is controversial at best. Most studies of proliferation or cytokine secretion defects in PBLs show demonstrable evidence, albeit diminished, of T‐cell activation, showing that T‐cell signaling is occurring and thus T cells do not lack TCRζ.…”

Section: Tumor‐induced Loss Of Proximal Tcr Signaling Moleculesmentioning

confidence: 85%

“…Antigen‐specific memory effector or effector CD8 + anti‐tumor T cells home to tumor, implying that T‐cell effector phase function is suppressed in situ . Our laboratory has investigated the biochemical basis for TIL lytic dysfunction (11, 20, 52, 73–75, 91, 148). Like TILs in situ , TILs freshly isolated from a murine colorectal carcinoma (MCA38) are not apoptotic but are non‐lytic (75) and have cell cycle arrest being predominately in G 1 (149).…”

Section: Tumor‐induced Inhibitory Signaling Blocks Til Lytic Functionmentioning

confidence: 99%

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Signaling defects in anti‐tumor T cells

Frey

Monu

2008

Immunological Reviews

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The immune response to cancer has been long recognized, including both innate and adaptive responses, showing that the immune system can recognize protein products of genetic and epigenetic changes in transformed cells. The accumulation of antigen-specific T cells within the tumor, the draining lymph node, and the circulation, either in newly diagnosed patients or resultant from experimental immunotherapy, proves that tumors produce antigens and that priming occurs. Unfortunately, just as obviously, tumors grow, implying that anti-tumor immune responses are either not sufficiently vigorous to eliminate the cancer or that anti-tumor immunity is suppressed. Both possibilities are supported by current data. In experimental animal models of cancer and also in patients, systemic immunity is usually not dramatically suppressed, because tumor-bearing animals and patients develop T-cell-dependent immune responses to microbes and to either model antigens or experimental cancer vaccines. However, inhibition of specific anti-tumor immunity is common, and several possible explanations of tolerance to tumor antigens or tumor-induced immunesuppression have been proposed. Inhibition of effective anti-tumor immunity results from the tumor or the host response to tumor growth, inhibiting the activation, differentiation, or function of anti-tumor immune cells. As a consequence, anti-tumor T cells cannot respond productively to developmental, targeting, or activation cues. While able to enhance the number and phenotype of anti-tumor T cells, the modest success of immunotherapy has shown the necessity to attempt to reverse tolerance in anti-tumor T cells, and the vanguard of experimental therapy now focuses on vaccination in combination with blockade of immunosuppressive mechanisms. This review discusses several potential mechanisms by which anti-tumor T cells may be inhibited in function.

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Section: Tumor‐induced Loss Of Proximal Tcr Signaling Moleculesmentioning

confidence: 85%

Section: Tumor‐induced Inhibitory Signaling Blocks Til Lytic Functionmentioning

confidence: 99%

Signaling defects in anti‐tumor T cells

Frey

Monu

2008

Immunological Reviews

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“…This notion has since been generally discounted since multiple findings in several laboratories did not replicate the absence of TCR in TIL (reviewed in Ref. [21]). At that time, seeking to ascertain the basis for dysfunctional antitumor immunity in cancer patients, several laboratories analyzed peripheral blood T cells for the level of TCR, which was found to be deficient [22,23].…”

Section: Systemic Antitumor Immune Responsementioning

confidence: 97%

Suppression of T cell responses in the tumor microenvironment

Frey

2015

Vaccine

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“…Thus, preventing or delaying functional loss and endowing reactive T cells with the capacity to maintain antitumor effector functions longer in the tumor environment are imperatives for achieving more effective T-cell response. Functional inactivation may occur due to blockade of TCR signaling, loss of cytotoxic proteins, lack of persistence, and functional polarization from an antitumor Th1 to a less favorable Th2 phenotype (15)(16)(17)(18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

Chimeric PD-1:28 Receptor Upgrades Low-Avidity T cells and Restores Effector Function of Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy

et al. 2017

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Inherent intermediate-to low-affinity T-cell receptors (TCR) that develop during the natural course of immune responses may not allow sufficient activation for tumor elimination, making the majority of T cells suboptimal for adoptive T-cell therapy (ATT). TCR affinity enhancement has been implemented to provide stronger T-cell activity but carries the risk of creating undesired cross-reactivity leading to potential serious adverse effects in clinical application. We demonstrate here that engineering of low-avidity T cells recognizing a naturally processed and presented tumor-associated antigen with a chimeric PD-1:28 receptor increases effector function to levels seen with high-avidity T cells of identical specificity. Upgrading the function of low-avidity T cells without changing the TCR affinity will allow a large arsenal of low-avidity T cells previously thought to be therapeutically inefficient to be considered for ATT. PD-1:28 engineering reinstated Th1 function in tumor-infiltrating lymphocytes that had been functionally disabled in the human renal cell carcinoma environment without unleashing undesired Th2 cytokines or IL10. Involved mechanisms may be correlated to restoration of ERK and AKT signaling pathways. In mouse tumor models of ATT, PD-1:28 engineering enabled low-avidity T cells to proliferate stronger and prevented PD-L1 upregulation and Th2 polarization in the tumor milieu. Engineered T cells combined with checkpoint blockade secreted significantly more IFNg compared with T cells without PD-1:28, suggesting a beneficial combination with checkpoint blockade therapy or other therapeutic strategies. Altogether, the supportive effects of PD-1:28 engineering on T-cell function make it an attractive tool for ATT. Cancer Res; 77(13); 3577-90. Ó2017 AACR.

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Cancer-Induced Signaling Defects in Antitumor T Cells

Cited by 7 publications

References 146 publications

Signaling defects in anti‐tumor T cells

Signaling defects in anti‐tumor T cells

Suppression of T cell responses in the tumor microenvironment

Chimeric PD-1:28 Receptor Upgrades Low-Avidity T cells and Restores Effector Function of Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy

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