Interleukin-2 with Ex Vivo Activated Killer Cells: Therapy of Advanced Non-Small-Cell Lung Cancer

Bernstein, Zale P.; Goldrosen, Martin H.; Vaickus, Louis; Friedman, Nir; Watanabe, Hirotaka; Rahman, Rakhshanda Layeequr; Park, J.; Arbuck, Susan G.; Sweeney, Jennifer; Vesper, D; Takita, Hiroshi; Zeffren, J.; Dennin, R; Foon, Kenneth A.

doi:10.1097/00002371-199110000-00012

“…Since clonal proliferation is fundamental to the generation of an immune response, these observations indicated a diminution in the normal functions of T cells in DL‐bearing mice. Indeed, a defect in T‐cell proliferation with the growth of other types of malignancies has also been reported by other workers [18–20]. In the next part of our investigation, we studied whether this T‐cell proliferative defect was restricted to the non‐specific blastogenic response or whether the antigen‐specific T‐cell proliferative ability representing the fundamental T H function was also aberrant.…”

Section: Discussionsupporting

confidence: 67%

Impairment of T-cell functions with the progressive ascitic growth of a transplantable T-cell lymphoma of spontaneous origin

Shanker

¹

,

Singh

²

2000

FEMS Immunology &Amp; Medical Microbiology

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It has been observed that the progressive ascitic growth of a transplantable T-cell lymphoma of spontaneous origin, designated Dalton's lymphoma (DL), in a murine host induces inhibition of various immune responses and is associated with an involution of thymus accompanied by a massive depletion of the cortical region and alteration in the distribution of thymocytes caused by tumour serum-dependent induction of apoptosis with a decrease of CD4(+)CD8(+), CD4(+)CD8(-) and CD4(-)CD8(+) thymocytes. Here, we report that thymocytes of DL-bearing mice are defective in their proliferative ability and in their response to non-specific mitogenic stimulus in vitro. Also, antigen-specific T-cell proliferative ability representing the fundamental T(H) function declines under DL-bearing conditions and upon treatment with serum of DL-bearing mice. Moreover, a significant inhibition of T-cell cytolytic activity with a decreased ability to produce interferon gamma is shown by the T cells of DL-bearing mice and by the T cells treated with DL-ascitic fluid, DL-conditioned medium or serum of DL-bearing mice. Further, addition of interleukin-2 and anti-interleukin-10 to the cultures of thymocytes treated with serum of DL-bearing mice is found to inhibit the induction of apoptosis in thymocytes, a phenomenon associated with the progression of DL growth. Analysis of the results indicates an immune deviation with the predominance of a T(H2)-type response with the progression of tumour. We further discuss the possible mechanisms that may explain the observed tumour-induced diminution of T-cell immunity.

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“…To explain tumour-induced diminution of T-cell immunity, a variety of mechanisms have been proposed including the secretion of immunosuppressive cytokines and other factors by tumour cells [27], diminished production of lymphokines and growth factors [28], induction of Tcell anergy [29], appearance of T-cell suppressor activities [30,31] and deletion of tumour-speci¢c clones [32]. The aforesaid T-cell defects may be associated with perturbations in the signal transduction pathway as a result of the defects in the constitution of the TCR-CD3 signalling complex such as the loss or abnormal expression of the CD3j chain with a defective extracellular domain [20,32,33], reduced expression of CD3-associated protein tyrosine kinases p 56Lck and p 59Fyn [34], loss of expression and/or nuclear translocation of downstream signalling molecule nuclear transcription factor NFUB p 65 [35] and increased nuclear accumulation of the transcription factor NFATc [36]. Tumour-induced changes in the macrophage accessory activities have also been shown to suppress Tcell recognition of allogeneic and syngeneic MHC class II molecules [37].…”

Section: Discussionmentioning

confidence: 99%

Impairment of T-cell functions with the progressive ascitic growth of a transplantable T-cell lymphoma of spontaneous origin

Shanker

¹

2000

FEMS Immunology and Medical Microbiology

View full text Add to dashboard Cite

It has been observed that the progressive ascitic growth of a transplantable T-cell lymphoma of spontaneous origin, designated Dalton's lymphoma (DL), in a murine host induces inhibition of various immune responses and is associated with an involution of thymus accompanied by a massive depletion of the cortical region and alteration in the distribution of thymocytes caused by tumour serum-dependent induction of apoptosis with a decrease of CD4(+)CD8(+), CD4(+)CD8(-) and CD4(-)CD8(+) thymocytes. Here, we report that thymocytes of DL-bearing mice are defective in their proliferative ability and in their response to non-specific mitogenic stimulus in vitro. Also, antigen-specific T-cell proliferative ability representing the fundamental T(H) function declines under DL-bearing conditions and upon treatment with serum of DL-bearing mice. Moreover, a significant inhibition of T-cell cytolytic activity with a decreased ability to produce interferon gamma is shown by the T cells of DL-bearing mice and by the T cells treated with DL-ascitic fluid, DL-conditioned medium or serum of DL-bearing mice. Further, addition of interleukin-2 and anti-interleukin-10 to the cultures of thymocytes treated with serum of DL-bearing mice is found to inhibit the induction of apoptosis in thymocytes, a phenomenon associated with the progression of DL growth. Analysis of the results indicates an immune deviation with the predominance of a T(H2)-type response with the progression of tumour. We further discuss the possible mechanisms that may explain the observed tumour-induced diminution of T-cell immunity.

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“…Thus, in patients with advanced SCLC who did not achieve a complete response after chemotherapy, IL-2 infusion could induce either complete remission or additional tumour regression in almost 20% of cases [128]. By contrast, marginal responses were achieved in patients with advanced NSCLC, a majority experiencing severe toxicity [120][121][122][123][124][125][126][127]. However, the therapeutic response appears to vary according to the anatomical site, suggesting a difference in susceptibility according to the location of the tumour.…”

Section: Cytokines Associated or Not With Adoptive Immunotherapy (Tabmentioning

confidence: 99%

Pulmonary perspective: immunology in diagnosis and treatment of lung cancer

Weynants

¹

,

Marchandise²,

Sibille³

1997

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Interleukin-2 with Ex Vivo Activated Killer Cells: Therapy of Advanced Non-Small-Cell Lung Cancer

Cited by 16 publications

References 0 publications

Impairment of T-cell functions with the progressive ascitic growth of a transplantable T-cell lymphoma of spontaneous origin

Impairment of T-cell functions with the progressive ascitic growth of a transplantable T-cell lymphoma of spontaneous origin

Impairment of T-cell functions with the progressive ascitic growth of a transplantable T-cell lymphoma of spontaneous origin

Pulmonary perspective: immunology in diagnosis and treatment of lung cancer

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