Mechanism of Immune Response During Immunotherapy

Abstract

Tumor immunology embraces an extensive array of biological phenomena that include interactions between neoplastic cells and the innate and adaptive immune response. Among immune cells, T cells have taken the center stage because they can be easily demonstrated to specifically recognize autologous cancer cells. However, their role is limited and other components of the immune response are likely necessary for the completion of cancer rejection. Metastatic melanoma and renal cell carcinoma (RCC) are malignancies strongly predisposed to regress in response to the systemic administration of high-dose interleukin (IL)-2. Several clinical Studies in extensive cohorts of patients have shown that this treatment can induce complete or partial clinical regressions of metastatic disease in 15 to 20% of patients who receive this treatment. Although IL-2 has direct pluri-potent effects on cells with immune and inflammatory function, it remains unexplained which cell subset is implicated in mediating tumor regression. In a quest to characterize the mechanism of action of IL-2 during the course of immunotherapy, we have investigated the early changes in transcriptional profiles of circulating mononuclear cells and microenvironment of melanoma metastases following high dose IL-2 administration (720,000 IU/kg) by serial sampling of blood cells and tumors in the form of fine needle aspirate (FNA). Furthermore, studies are currently ongoing to characterize the proteomic profiling of RCC patients undergoing the same treatment using protein arrays (manuscript in preparation). The predominant activation of genes related to inflammation and activation of mononuclear phagocytes lead us to further characterize this cell subset in the context of stimulation with a panel of soluble factors potentially present in the circulation and tumor microenvironment.

The 20th anniversary of interleukin-2 therapy: bimodal role explaining longstanding random induction of complete clinical responses

“…Genetic variations in tumors and in individual patient immune constitution/capability have been investigated in attempts to either predict responses or select patients for therapy. Although several factors, such as low serum levels of fibronectin and vascular endothelial growth factor, have been associated with improved responses to IL2, it has remained difficult to predict responders 23,24…”

Phenotype Analysis of Tumour-infiltrating Lymphocytes and Lymphocytes in Peripheral Blood in Patients with Renal Carcinoma

“…Our observations comply with this finding. The prevalence of CD3 + CD8 + cell population was also described in the stroma of other tumours (7,15,23,32,33). CD4 + T lymphocytes, which are the main producer of IL-2, show anti-tumour activity.…”