T cell functions of IL-2-activated tumor-infiltrating lymphocytes from renal cell carcinoma

Renal cell carcinoma (RCC) is one of the few cancers partially sensitive to biotherapy. However, involvement of T cell immunity in host-defense against autologous tumor cells remains unclear. This manuscript investigated T cell functions of interleukin-2 (IL-2)-activated tumor-infiltrating lymphocytes (TILs) from human RCCs by studying their oligoclonality, cytotoxicity, and cytokine production. IL-2-activated RCC-TILs from 17 of 33 cases (52%) (p < 0.01 vs. IL-2-activated patients' peripheral blood mononuclear cells, PBMC) displayed oligoclonal expansion as determined by seven different monoclonal antibodies (mAbs) to T cell receptor (TCR) V alpha or beta regions after 2 to 5 weeks in culture. By comparison, IL-2-activated PBMC from only 1 of 15 healthy donors (7%), 3 of 23 patients (13%), and IL-2-activated lymphocytes from nontumorous kidney from 1 of 8 (12.5%) cases (V beta 5.1) did. Specifically, IL-2-activated RCC-TILs showed oligoclonal expansion of V alpha 2+ cells (8/33 cases, p < 0.05 vs. IL-2-activated patient's PBMC), V beta 5.1+ cells (6/33), V beta 8+ cells (4/33), V beta 12+ cells (4/33), and V beta 6.7+ cells (2/33). Oligoclonal expansion of plural TCR V regions was observed in 6 of 33 cases. IL-2-activated RCC-TILs from 4 of 16 cases produced higher levels of interferon-gamma (IFN-gamma) in culture with autologous tumor cells than with allogeneic tumor cells. Those from 11 of 16 cases did not produce IFN-gamma in response to autologous tumor cells, and the remaining case produced it in a major histocompatibility complex (MHC)-nonrestricted manner. IL-2-activated RCC-TILs with oligoclonal expansion in 4 of 5 cases showed IFN-gamma production in response to the corresponding anti-TCR V region mAb as well as anti-CD3 mAb. IL-2 and IL-4 were not detected in any cases tested. IL-2-activated RCC-TILs displayed cytotoxicity relatively restricted to autologous tumor cells in only 1 of the 16 cases evaluated, MHC-nonrestricted cytotoxicity in 12 cases, NK activity in one case and no cytotoxicity in two cases. In summary, IL-2-activated RCC-TILs demonstrated the oligoclonality in approximately half of the cases (17 of 33, 52%), but rarely displayed either autologous tumor-specific-IFN-gamma production (4 of 16 cases) or -cytotoxicity (1 of 16 cases).