Targeting Molecular and Cellular Inhibitory Mechanisms for Improvement of Antitumor Memory Responses Reactivated by Tumor Cell Vaccine

Abstract

Development of effective vaccination approaches to treat established tumors represents a focus of intensive research because such approaches offer the promise of enhancing immune system priming against tumor Ags via restimulation of pre-existing (memory) antitumoral helper and effector immune cells. However, inhibitory mechanisms, which function to limit the recall responses of tumor-specific immunity, remain poorly understood and interfere with therapies anticipated to induce protective immunity. The mouse renal cell carcinoma (RENCA) tumor model was used to investigate variables affecting vaccination outcomes. We demonstrate that although a whole cell irradiated tumor cell vaccine can trigger a functional antitumor memory response in the bone marrows of mice with established tumors, these responses do not culminate in the regression of established tumors. In addition, a CD103+ regulatory T (Treg) cell subset accumulates within the draining lymph nodes of tumor-bearing mice. We also show that B7-H1 (CD274, PD-L1), a negative costimulatory ligand, and CD4+ Treg cells collaborate to impair the recall responses of tumor-specific memory T cells. Specifically, mice bearing large established RENCA tumors were treated with tumor cell vaccination in combination with B7-H1 blockade and CD4+ T cell depletion (triple therapy treatment) and monitored for tumor growth and survival. Triple treatment therapy induced complete regression of large established RENCA tumors and raised long-lasting protective immunity. These results have implications for developing clinical antitumoral vaccination regimens in the setting in which tumors express elevated levels of B7-H1 in the presence of abundant Treg cells.

Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1)

“…Moreover, it may dramatically improve the efficacy of any vaccination protocols targeting ALK or other lymphoma-related antigens. It seems relevant in this context that in the mouse model of renal cell carcinoma, the irradiated cancer-cell vaccine combined with an antibody-induced blockade of CD274, and depletion of regulatory cell-rich CD4 ϩ T cells resulted in complete tumor regression (36). This outcome indicates that combination therapy may be required to achieve long-lasting therapeutic effects in human malignancies including ALKϩTCL.…”

Targeting CD73 Enhances the Antitumor Activity of Anti-PD-1 and Anti-CTLA-4 mAbs

“…Concurrent blockade of CTLA-4 and PD-1 has also shown encouraging results in a phase I clinical trial (37). Studies have also tested the potential benefit of combining anti-PD-1 mAb with tumor vaccines (38,39) and low-dose Treg-depleting cyclophosphamide (40). In the latter setting, anti-PD-1 mAb was found to prolong the inhibition of Tregs by low-dose cyclophosphamide.…”

Eradication of established renal cell carcinoma by a combination of 5‐fluorouracil and anti‐4‐1BB monoclonal antibody in mice

“…Recently, several investigators have also reported that established tumors could be eradicated by CD4 1 depletion in various animal tumor models including Renca tumors. [25][26][27] Mice that have recovered from Renca tumors as a result of combination therapy have a long-lasting specific memory…”