Medicina Traslazionale

Patogenesi molecolare e risposta immune nel carcinoma renale: un esempio applicativo di medicina traslazionale

Prof.ssa Elena Ranieri

Cattedra di Patologia Clinica
Dipartimento di Scienze Biomediche
Università degli Studi di Foggia

Renal cell carcinoma: un modello di studio

• Renal cell carcinoma accounts for approximately 3% of adult malignancies and is the sixth leading cause of cancer death.
• Renal cell carcinoma may remain clinically occult for most of its course. The classic triad of flank pain, hematuria, and flank mass is uncommon (10%) and is indicative of advanced disease.
• 25-30% of patients are asymptomatic, and their renal cell carcinomas are found on incidental radiologic study.
• It is characterized by resistance to radiation and chemotherapy, and infrequent but reproducible responses to immunotherapy agents such as interferon alpha and interleukin-2.

Istopatologia del carcinoma renale

• Ritenendo che il tumore renale originasse da residui della ghiandola surrenale, in passato veniva definito ipernefroma.
• Agli inizi degli anni '60, la dimostrazione della sua origine dai tubuli renali portò alla definizione di una singola entità denominata adenocarcinoma renale, distinto nelle seguenti forme (classificazione di Mainz):
• A cellule chiare (70%)
• A cellule cromofile (15%)
• A cellule cromofobe (5%)
• Carcinoma dei dotti collettori (2%)

Renal cell carcinoma

• RCC belongs to a small group of cancers where immune-mediated mechanisms play important roles in limiting tumor growth.
• Patients with active, disseminated disease are typically characterized by predominant Th2- or T regulatory-type immunity.
• RCC lesions contain tumor-infiltrating lymphocytes reported to be “functionally inappropriate”, dysfunctional or pro-apoptotic.

Tatsumi, T., Kierstead, L.S., Ranieri, E., Gesualdo, et al, J Exp Med, 2003

Renal cell carcinoma (RCC)

In RCC spontaneous tumor regression can be observed, although in rare cases, in metastatic disease. This suggests that RCC expresses tumor antigens specifically recognized by T cells. Immune mechanisms play a role in limiting tumor growth.

Finke J., L.S. Kierstead, E. Ranieri, W.J. Storkus, Humana Press, 2000

Mechanisms of tumor evasion

Mapara MY et al J Clin Oncol, 2004

Mediators of immune defense

• Dendritic Cell
• Innate
• Adaptive
• Macrophages
• Antibodies
• T-Lymphocytes
• Cytokines
• NK cells
• B CTL NKTregTh Tumor

Study design

• DC specific T cell immune response
• Identification of immunogenic RCC cell lines
• Immunotherapy
• Molecular pathogenesis and drugs
• Biomarkers identification
• Diagnosis/monitoring of disease

Dendritic cells and immune responses

Dendritic cell biology

DCs are the most potent antigen-presenting cells that play a central role in coordinating human immunity. They comprise different subsets at different stages of maturation.