Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25

Abstract

The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated longterm control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4 + T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of CTLA-4 block-

Immunological markers and clinical outcome of advanced melanoma patients receiving ipilimumab plus fotemustine in the NIBIT-M1 study

“…Recently, it has been reported that soluble CD25 (IL-2Ra) in baseline serum represented an independent indicator of OS for MM patients undergoing IPI therapy, highlighting the need to further investigate the role of soluble molecules as biomarkers for this therapy. 48 Notably, we could identify at baseline an inverse correlation between the absence of sNKG2DLs in the serum and the enrichment of few circulating T cell subsets (e.g., CD3 C CD4 C CD45RO C BTLA C , CD3 C CD4 C 4-1BB C , and Th17) in MM patients with clinical responses to IPI plus FTM regimen.…”

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

“…Elevated baseline soluble CD25 appeared to be associated with shorter OS, although the small number of patients precludes a definitive conclusion; however, in a larger series of patients treated with ipilimumab, baseline serum concentrations of sCD25 represented an independent indicator of OS, with high levels predicting resistance to therapy. 22 A mechanistic basis for this observation relates to findings that decoy sCD25 in mouse studies inhibits anti-tumor effects of CTLA4 blockade. 22 Thus, it appears that our findings regarding baseline sCD25 reflect the use of tremelimumab in the treatment schema (more likely than a relation to CD40 mAb) and indicates that baseline sCD25 as a negative predictor of survival following treatment with ipilimumab or tremelimumab may be a class effect.…”

“…22 A mechanistic basis for this observation relates to findings that decoy sCD25 in mouse studies inhibits anti-tumor effects of CTLA4 blockade. 22 Thus, it appears that our findings regarding baseline sCD25 reflect the use of tremelimumab in the treatment schema (more likely than a relation to CD40 mAb) and indicates that baseline sCD25 as a negative predictor of survival following treatment with ipilimumab or tremelimumab may be a class effect. Additional studies are needed to see if sCD25 may be a useful biomarker in patients with cancers other than melanoma and treated with CTLA-4 inhibitors.…”

IL-15 Trans-Signaling with the Superagonist RLI Promotes Effector/Memory CD8+ T Cell Responses and Enhances Antitumor Activity of PD-1 Antagonists

“…We took advantage of two well-known immunogenic solid tumor models in mice, CT26 and MC38. These tumors are controlled by CD8 + T cells thus prone to respond to immunotherapy (14,17,22,23). Moreover, studies in mice have shown a link between mutational load of the tumor and clinical efficacy of immunotherapy (24).…”

“…Tumor models, tumor inoculation in mice, and antitumor treatments CT26 and MC38 are two immunogenic tumor models controlled by CD8 + T cells and known to respond to immune checkpoint blockers such as anti-PD-1 (14)(15)(16)(17) Mouse single cell preparation from spleen, lymph node, lung, bone marrow, and tumors Spleen and lymph nodes. Single cells were obtained after mechanical disruption, and RBCs were lysed using ACK lysing buffer (spleen).…”