Clonal analysis of cytotoxic and regulatory T cell responses against human melanoma.

Abstract

Studies of T cell-mediated immune response against spontaneously arising autologous human tumors have been markedly facilitated by functional analyses of T cells at the clonal level (1-7). This particular approach has now provided a strong support for the long-held belief by some, although viewed skeptically by others, that T cell-mediated host responses do indeed exist in different types ofhuman cancers. The evidence for such T cell antitumor response has been particularly impressive in malignant melanoma (1-4, 6, 7). In this system, the existence of CTL response (1-4, 6, 7), proliferative T cell response (8, 9), suggestion for regulatory T cell response (10, 11), and delayed-type hypersensitivity response (12) have all been demonstrated. While this impressive body of evidence certainly represents a serious beginning in investigation on T cell responses against autologous cancer, a critical analysis ofT cell-immune responses against a large number ofautologous melanoma at clonal levels is necessary for a more comprehensive understanding of T cell-immune response in host defense against human cancers or, for that matter, against malignant melanoma .We have undertaken clonal analyses of T cell-immune response in a larger group of patients with melanoma . In this work, we present our observation of clonal analyses of CTL and regulatory responses in 31 autologous case studies. Here we show that T cell responses (CTL as well as regulatory T cell responses), taken together, are demonstrable in approximately half of this cohort of subjects. Results of our studies clearly document the involvement of the entire T cell repertoire in response to autologous melanoma . The melanoma-specific (CTL) responses show appropriate MHC class restriction, and the cytotoxic response in the PBL is subject to regulation by the helper and suppressor arms of the T cell network. The amplification of cytotoxic response by Th cell clones is mediated by the elaboration of IL-2 and IFN-y, and the T cell-mediated downregulatory responses can be specific as well as nonspecific.

Sunitinib Reverses Type-1 Immune Suppression and Decreases T-Regulatory Cells in Renal Cell Carcinoma Patients

“…Treg cells are known to suppress T-cell function (10,16,17) and are reported to be elevated in mRCC patients (34, 35). Four-color analysis of PBMC from patients in this study (n = 34) confirmed that mRCC patients have elevated levels of CD3 (Fig.…”

“…The frequency of Treg cells is elevated in tumor sites and/or the peripheral blood of patients with advanced tumors (11 -15). Treg cells can impair induction of both antigen-specific and nonspecific T cells in melanoma patients (16,17) and predict reduced survival in multiple cancer cell types (13, 18 -20). Relevant to therapy, experimental models have shown that removal of Treg cells modifies the immune response to tumors.…”

Studies of the mechanism of cytolysis by tumour-infiltrating lymphocytes

“…In malignant melanoma, it has been shown that TIL are able to recognize tumour-associated antigens, and in some cases to lyse the malignant cells [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. These findings provided a basis for the use of in vitro cultured TIL in adoptive immunotherapy in an effort to enhance the in vivo accumulation of tumour-lytic lymphocytes [29,31].…”

Varicella zoster virus infection associated with high-dose chemotherapy and autologous stem-cell rescue

“…Cells were harvested in a Titertek semi-automatic cell harvester (Skattron, Sterling, VA, USA) and thymidine incorporation was estimated by a Beckman liquid scintillation counter (Beckman Instruments, Irvine, CA, USA). 6 …”