Abstract
Allogeneic cell therapy as a means to break immunotolerance to solid tumors is increasingly used for cancer treatment. To investigate cellular alloimmune responses in a human tumor model, primary cultures were established from renal cell carcinoma (RCC) tissues of 56 patients. In three patients with stable RCC line and human leukocyte antigen (HLA)-identical sibling donor available, allogeneic and autologous RCC reactivities were compared using mixed lymphocyte/tumor cell cultures (MLTC). Responding lymphocytes were exclusively CD8(+) T cells, whereas CD4(+) T cells or natural killer cells were never observed. Sibling MLTC populations showed higher proliferative and cytolytic antitumor responses compared with their autologous counterparts. The allo-MLTC responders originated from the CD8(+) CD62L(high)(+) peripheral blood subpopulation containing naive precursor and central memory T cells. Limiting dilution cloning failed to establish CTL clones from autologous MLTCs or tumor-infiltrating lymphocytes. In contrast, a broad panel of RCC-reactive CTL clones was expanded from each allogeneic MLTC. These sibling CTL clones either recognized exclusively the original RCC tumor line or cross-reacted with nonmalignant kidney cells of patient origin. A minority of CTL clones also recognized patient-derived hematopoietic cells or other allogeneic tumor targets. The MHC-restricting alleles for RCC-reactive sibling CTL clones included HLA-A2, HLA-A3, HLA-A11, HLA-A24, and HLA-B7. In one sibling donor-RCC pair, strongly proliferative CD3(+)CD16(+)CD57(+) CTL clones with non-HLA-restricted antitumor reactivity were established. Our results show superior tumor-reactive CD8 responses of matched allogeneic compared with autologous T cells. These data encourage the generation of antitumor T-cell products from HLA-identical siblings and their potential use in adoptive immunotherapy of metastatic RCC patients.
Highlights
Treatment options for patients with metastatic renal cell carcinoma (RCC) are limited mainly because this cancer is resistant to conventional chemotherapy
Compared with Nonmalignant kidney cells (NKC) counterparts, RCC cells expressed higher levels of surface human leukocyte antigen (HLA) class I complexes under basal conditions
We have recently shown that RCC-reactive CTL clones can be isolated from unrelated healthy donors matched with previously established RCC stimulator cell lines for HLA class I [23]
Summary
Treatment options for patients with metastatic renal cell carcinoma (RCC) are limited mainly because this cancer is resistant to conventional chemotherapy. Doi:10.1158/0008-5472.CAN-06-0998 responses are obtained after cytokine-based immunotherapy, with 10% to 20% of patients showing partial or complete tumor remissions [1]. This observation established the concept that RCC is an immunogenic tumor. Based on CTLs and TILs expanded from patient blood and tumor tissue samples, a few T-cell-defined RCC antigens have been identified. These epitopes are derived either from nonmutated proteins [6] or from mutated [7, 8] or alternatively processed gene products [9, 10]. Several predicted epitopes were successfully used to stimulate RCC-reactive CD4+ and CD8+ T cells in vitro [11,12,13,14,15]
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