Intra-tumoral cytolytic cells: Pattern of distribution in B-cell non Hodgkin’s lymphoma

Perambakam, Supriya; Naresh, Kikkeri N.; Nerurkar, Ashutosh; Nadkarni, Jayshree J.

doi:10.1007/bf03032360

Cited by 7 publications

(5 citation statements)

References 11 publications

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“…In preliminary experiments, we have shown apoptosis of B‐CLL tumour cells as determined by Annexin V binding by freshly isolated CD4 + T cells through CD3xCD19 bispecific antibodies. Interestingly, there are also now reports of the cytotoxicity‐related molecule TiA by CD4 + as well as CD8 + cells in non‐Hodgkin lymphomas and other lymphomas ([29] and A. Dogan, personal communication), suggesting that they may have a role in other lymphoid malignancies.…”

Section: Discussionmentioning

confidence: 99%

Expansion of CD4+ T cells with a cytotoxic phenotype in patients with B-chronic lymphocytic leukaemia (B-CLL)

Porakishvili¹,

Roschupkina

Kalber

et al. 2001

Clinical and Experimental Immunology

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SUMMARYAbnormal CD4/CD8 ratios and T-cell function have previously been shown in patients with B-chronic lymphocytic leukaemia (B-CLL). We have demonstrated that CD4 1 T cells containing both serine esterase and perforin (PF) are increased in the blood of these patients. Using flow cytometry, we have shown that the CD4 1 PF 1 cells were CD57 1 but lacked expression of CD28, suggesting a mature population. The same phenotype in CD8 1 T cells is characteristic of mature cytotoxic T cells. However, in contrast to the CD8 1 T cells, the CD4 1 T cells were more frequently CD45RO positive than CD45RA positive, indicating prior antigen experience. In contrast, this population lacked expression of either CD69 or HLA-DR, arguing that they were not activated or that they are an abnormal population of T cells. Their constitutive cytokine levels showed them mainly to contain IL4 and not IFNg, suggesting a Th2 phenotype. The role of the CD4 1 PF 1 T-cell population is at present uncertain. However, this potentially cytotoxic T-cell population could contribute both to enhancing survival of the B-CLL tumour cells through production of IL4, and to the immunodeficient state frequently seen in patients with this tumour, independent of drug treatment.

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Section: Discussionmentioning

confidence: 99%

Expansion of CD4+ T cells with a cytotoxic phenotype in patients with B-chronic lymphocytic leukaemia (B-CLL)

Porakishvili¹,

Roschupkina

Kalber

et al. 2001

Clinical and Experimental Immunology

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“…NK cells are important components of the innate immune response against malignant cells. In FL, NK cell amount in peripheral blood is associated with clinical outcomes as low cell number correlates with worse overall survival and shorter time to progression (22, 23). This seems to be correlated with a decrease of RTX mediated ADCC in FL patients (41).…”

Section: Discussionmentioning

confidence: 99%

“…Their low count in the peripheral blood of FL patients is correlated with poor prognosis, strongly supporting their key role for therapy (21, 22). In infiltrated lymph nodes and follicles of FL patients, NK cells are present (23), but their cytotoxic status and the modelization of their function in a relevant FL model are unexplored. We are pioneer in the development of 3D FL in vitro model, called MALC.…”

Section: Introductionmentioning

confidence: 99%

A Tridimensional Model for NK Cell-Mediated ADCC of Follicular Lymphoma

et al. 2019

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Follicular lymphoma (FL) is the second most frequent subtype of B non-Hodgkin's lymphomas (NHL) for which the treatment is based on the use of anti-CD20 mAbs. NK cells play a crucial role in their mechanism of action and the number of these cells mediating antibody-dependent cell cycotoxicity (ADCC) in the peripheral blood of FL patients predict the outcome. However, their presence in FL biopsies, their activation and their role have been poorly investigated. Moreover, in vitro studies have not deciphered the exact signaling cascades triggered by NK cells in presence of anti-CD20 mAbs on both effector and target cells in a relevant FL model. We performed in silico analyses and ex vivo functional assays to determine the presence and the activation status of NK cells in FL biopsies. We modelized ADCC phenomenon by developing a co-culture model composed by 3D-cultured FL cells and NK cells. Thus, we investigated the biological effect of anti-CD20 mAbs by fluorescent microscopy and the phosphorylation status of survival pathways by cell bar coding phosphoflow in target cells. In parallel, we measured the status of activation of downstream FcγRIIIa signaling pathways in effector cells and their activation (CD69, perforin, granzyme B, IFNγ) by flow cytometry. We determined by in vivo experiments the effects of anti-CD20 mAbs in presence of NK cells in SCID-Beige engrafted FL mice. Here, we show that functional NK cells infiltrate FL biopsies, and that their presence tends to correlate with the survival of FL patients. Using our 3D co-culture model, we show that rituximab and GA101 are able to promote degranulation, CD69 expression, IFNγ production and activate FcγRIIIa signaling cascade in NK cells, and inhibit survival pathways and induce apoptosis in FL cells. The effect of GA101 seems to be more pronounced as observed in vivo in a xenograft FL model. This study strongly supports the role of NK cells in FL and highlights the application of the 3D co-culture model for in vitro validation.

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“…Besides cytotoxic effector functions, activated NK cells can produce high levels of cytokines, which may in turn lead to further activation of several immune cell types including T cells (8). Previous studies have shown that cytotoxic lymphocytes predominantly reside at the periphery of follicles and in the interfollicular areas close to T cells (24). In this compartment, the interplay with T cells secreting IL-2 leads to NK cell-mediated release of IFNγ (14).…”

Section: Discussionmentioning

confidence: 99%

Systemic and Intra-Nodal Activation of NK Cells After Rituximab Monotherapy for Follicular Lymphoma

et al. 2019

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Monotherapy with the anti-CD20 monoclonal antibody rituximab can induce complete responses (CR) in patients with follicular lymphoma (FL). Resting FcRγIII+ (CD16+) natural killer (NK) cells respond strongly to rituximab-coated target cells in vitro. Yet, the contribution of NK cells in the therapeutic effect in vivo remains unknown. Here, we followed the NK cell repertoire dynamics in the lymph node and systemically during rituximab monotherapy in patients with FL. At baseline, NK cells in the tumor lymph node had a naïve phenotype albeit they were more differentiated than NK cells derived from control tonsils as determined by the frequency of CD56dim NK cells and the expression of killer cell immunoglobulin-like receptors (KIR), CD57 and CD16. Rituximab therapy induced a rapid drop in NK cell numbers coinciding with a relative increase in the frequency of Ki67+ NK cells both in the lymph node and peripheral blood. The Ki67+ NK cells had slightly increased expression of CD16, CD57 and higher levels of granzyme A and perforin. The in vivo activation of NK cells was paralleled by a temporary loss of in vitro functionality, primarily manifested as decreased IFNγ production in response to rituximab-coated targets. However, patients with pre-existing NKG2C+ adaptive NK cell subsets showed less Ki67 upregulation and were refractory to the loss of functionality. These data reveal variable imprints of rituximab monotherapy on the NK cell repertoire, which may depend on pre-existing repertoire diversity.

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Intra-tumoral cytolytic cells: Pattern of distribution in B-cell non Hodgkin’s lymphoma

Cited by 7 publications

References 11 publications

Expansion of CD4+ T cells with a cytotoxic phenotype in patients with B-chronic lymphocytic leukaemia (B-CLL)

Expansion of CD4+ T cells with a cytotoxic phenotype in patients with B-chronic lymphocytic leukaemia (B-CLL)

A Tridimensional Model for NK Cell-Mediated ADCC of Follicular Lymphoma

Systemic and Intra-Nodal Activation of NK Cells After Rituximab Monotherapy for Follicular Lymphoma

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