RESUMO
The potent anti-tumour activities of gammadelta T cells have prompted the development of protocols in which gammadelta-agonists are administered to cancer patients. Encouraging results from small Phase I trials have fuelled efforts to characterize more clearly the application of this approach to unmet clinical needs such as metastatic carcinoma. To examine this approach in breast cancer, a Phase I trial was conducted in which zoledronate, a Vgamma9Vdelta2 T cell agonist, plus low-dose interleukin (IL)-2 were administered to 10 therapeutically terminal, advanced metastatic breast cancer patients. Treatment was well tolerated and promoted the effector maturation of Vgamma9Vdelta2 T cells in all patients. However, a statistically significant correlation of clinical outcome with peripheral Vgamma9Vdelta2 T cell numbers emerged, as seven patients who failed to sustain Vgamma9Vdelta2 T cells showed progressive clinical deterioration, while three patients who sustained robust peripheral Vgamma9Vdelta2 cell populations showed declining CA15-3 levels and displayed one instance of partial remission and two of stable disease, respectively. In the context of an earlier trial in prostate cancer, these data emphasize the strong linkage of Vgamma9Vdelta2 T cell status to reduced carcinoma progression, and suggest that zoledronate plus low-dose IL-2 offers a novel, safe and feasible approach to enhance this in a subset of treatment-refractory patients with advanced breast cancer.
Assuntos
Neoplasias da Mama/terapia , Difosfonatos/uso terapêutico , Imidazóis/uso terapêutico , Imunoterapia/métodos , Interleucina-2/uso terapêutico , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Subpopulações de Linfócitos T/citologia , Adjuvantes Imunológicos/efeitos adversos , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/uso terapêutico , Idoso , Neoplasias da Mama/sangue , Neoplasias da Mama/imunologia , Proliferação de Células/efeitos dos fármacos , Quimiocinas/sangue , Citocinas/sangue , Difosfonatos/efeitos adversos , Difosfonatos/farmacologia , Progressão da Doença , Esterases/metabolismo , Feminino , Hemiterpenos/farmacologia , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacologia , Interferon gama/metabolismo , Interleucina-2/efeitos adversos , Interleucina-2/farmacologia , Antígenos Comuns de Leucócito/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Contagem de Linfócitos , Lisina/análogos & derivados , Lisina/metabolismo , Pessoa de Meia-Idade , Mucina-1/sangue , Compostos Organofosforados/farmacologia , Indução de Remissão , Terapia de Salvação , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Resultado do Tratamento , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Ácido ZoledrônicoRESUMO
In humans, the selective depletion of CD8+ cells may prevent GVHD after allogeneic transplantation. These cells can infiltrate and damage target tissues. It is of interest to investigate the phenotypical characteristics and cytotoxic properties of the different CD8+ subsets in cGVHD patients. In a preliminary study we found that patients with cGVHD had a markedly elevated percentage of peripheral blood CCR7-/CD45RA+ cells compared to patients without cGVHD; conversely, the CCR7+/CD45RA+ subsets of CD8+ cells was significantly decreased. In this study, we report in depth on the phenotype of effector T cell subsets in cGVHD patients, as well as their proliferative capability, cytotoxic properties and cellular turnover. We confirm a predominance of effector T cell subsets in cGVHD patients and show that a large fraction of these cells down-regulate CCR7 and re-express CD45RA, thus approaching end-stage differentiation. Moreover CD8+ cells of cGVHD patients have low CD8 coreceptor expression, reduced proliferative potential and a high content of perforin and granzyme A. They also have a lower cell turnover and have more propensity to apoptosis, as demonstrated by BrdU incorporation. Taken together, our findings indicate a perturbation of the balance between naive/memory and effector/CD45RA+ CD8+ T cells, and suggest an involvement of the latter compartment characterized by a high content of cytotoxic equipment, in the pathogenesis of cGVHD.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Doença Enxerto-Hospedeiro/imunologia , Memória Imunológica , Idoso , Linfócitos T CD8-Positivos/química , Linfócitos T CD8-Positivos/classificação , Doença Crônica , Feminino , Granzimas/análise , Humanos , Antígenos Comuns de Leucócito/análise , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Perforina/análise , Receptores CCR7/análiseRESUMO
In this study we have evaluated the in vitro effects of four different aminobisphosphonates, alendronate, risedronate, neridronate and zoledronate, on Vgamma9Vdelta2 T cell activation and differentiation. All tested aminobisphosphonates induce an IL-2-dependent activation and expansion of Vgamma9Vdelta2 T lymphocytes in primary PBMC cultures of healthy donors. Most notably, they also determine a different distribution of Vgamma9Vdelta2 T cell subsets, with decrease of T(naive) and T(CM) cells and increase of T(EM) and T(EMRA) Vgamma9Vdelta2cells, indicating that in vitro treatment with aminobisphosphonates induces Vgamma9Vdelta2 T lymphocytes to differentiate towards an effector/cytotoxic phenotype. Accordingly, Vgamma9Vdelta2 T lymphocytes cultured with aminobisphosphonates and IL-2 showed a major content of IFN-gamma and acquired the ability to kill tumor target cells.