Abstract
Cancer immunotherapy is undergoing significant progress due to recent clinical successes by refined adoptive T-cell transfer and immunostimulatory monoclonal Ab (mAbs). B16F10-derived OVA-expressing mouse melanomas resist curative immunotherapy with either adoptive transfer of activated anti-OVA OT1 CTLs or agonist anti-CD137 (4-1BB) mAb. However, when acting in synergistic combination, these treatments consistently achieve tumor eradication. Tumor-infiltrating lymphocytes that accomplish tumor rejection exhibit enhanced effector functions in both transferred OT-1 and endogenous cytotoxic T lymphocytes (CTLs). This is consistent with higher levels of expression of eomesodermin in transferred and endogenous CTLs and with intravital live-cell two-photon microscopy evidence for more efficacious CTL-mediated tumor cell killing. Anti-CD137 mAb treatment resulted in prolonged intratumor persistence of the OT1 CTL-effector cells and improved function with focused and confined interaction kinetics of OT-1 CTL with target cells and increased apoptosis induction lasting up to six days postadoptive transfer. The synergy of adoptive T-cell therapy and agonist anti-CD137 mAb thus results from in vivo enhancement and sustainment of effector functions.
Highlights
Cancer immunotherapy is undergoing significant progress due to recent clinical successes by refined adoptive T-cell transfer and immunostimulatory monoclonal Ab
In this study we observed effective synergism of cytotoxic T lymphocytes (CTLs) infusion combined with anti-CD137 mAb treatment, resulting in complete regression of s.c. and efficient growth control of intradermal B16F10-OVA melanoma tumors in a CD4 and NK cell independent fashion
When treatment is postponed to day +7, the therapy loses efficacy probably as a result of immunosuppressive mechanisms deployed by the larger tumor [30] and because the rapidly increasing tumor cell burden overwhelms the immunotherapeutic regimen despite transient increases in CTL tumor infiltration
Summary
Cancer immunotherapy is undergoing significant progress due to recent clinical successes by refined adoptive T-cell transfer and immunostimulatory monoclonal Ab (mAbs). B16F10-derived OVAexpressing mouse melanomas resist curative immunotherapy with either adoptive transfer of activated anti-OVA OT1 CTLs or agonist anti-CD137 (4-1BB) mAb. when acting in synergistic combination, these treatments consistently achieve tumor eradication. Tumor-infiltrating lymphocytes that accomplish tumor rejection exhibit enhanced effector functions in both transferred OT-1 and endogenous cytotoxic T lymphocytes (CTLs). This is consistent with higher levels of expression of eomesodermin in transferred and endogenous CTLs and with intravital live-cell two-photon microscopy evidence for more efficacious CTL-mediated tumor cell killing. The synergy of adoptive T-cell therapy and agonist anti-CD137 mAb results from in vivo enhancement and sustainment of effector functions. Flow-cytometry of tumor-rejecting lymphocyte infiltrates and intravital microscopy of tumors provide evidence that anti-CD137 mAb therapy sustained the efficacy of more focused anti-tumor CTLs
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