Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8+ T cells directly within the tumor microenvironment

Journal for ImmunoTherapy of Cancer

Thomas F Gajewski¹  Robert Newton³  Peggy A Scherle³  Brendan Horton²  Holly K Koblish³  Stefani Spranger² 

[1] Department of Medicine, University of Chicago, Chicago, IL 60637, USA;Department of Pathology, University of Chicago, 5841 S. Maryland Ave, Chicago, IL 60637, USA;Incyte Corporation, Wilmington, DE 19880, USA

关键词: Immune inhibitory pathways;    Tumor microenvironment;    T cell anergy/exhaustion;    Tumor-infiltrating lymphocytes;    Combinatorial immunotherapy;    IDO inhibitor;    PD-1/PD-L1;    Anti-CLTA-4;   

Others  :  814756
DOI  :  10.1186/2051-1426-2-3

 received in 2013-10-29, accepted in 2014-01-22,  发布年份 2014

【 摘 要 】

Background

Blockade of immune inhibitory pathways is emerging as an important therapeutic modality for the treatment of cancer. Single agent treatments have partial anti-tumor activity in preclinical models and in human cancer patients. Inasmuch as the tumor microenvironment shows evidence of multiple immune inhibitory mechanisms present concurrently, it has been reasoned that combination therapies may be required for optimal therapeutic effect.

Methods

To test this notion, we utilized permutations of anti-CTLA-4 mAb, anti-PD-L1 mAb, and/or the IDO inhibitor INCB23843 in the murine B16.SIY melanoma model.

Results

All three combinations showed markedly improved tumor control over single treatments, with many mice achieving complete tumor rejection. This effect was seen in the absence of vaccination or adoptive T cell therapy. The mechanism of synergy was investigated to examine the priming versus effector phase of the anti-tumor immune response. Only a minimal increase in priming of anti-tumor T cells was observed at early time points in the tumor-draining lymph nodes (TdLN). In contrast, as early as three days after therapy initiation, a marked increase in the capacity of tumor-infiltrating CD8⁺ T cells to produce IL-2 and to proliferate was found in all groups treated with the effective combinations. Treatment of mice with FTY720 to block new T cell trafficking from secondary lymphoid structures still enabled restoration of IL-2 production and proliferation by intratumoral T cells, and also retained most of the tumor growth control.

Conclusions

Our data suggest that the therapeutic effect of these immunotherapies was mainly mediated through direct reactivation of T cells in situ. These three combinations are attractive to pursue clinically, and the ability of intratumoral CD8⁺ T cells to produce IL-2 and to proliferate could be an important biomarker to integrate into clinical studies.

【 授权许可】

   
2014 Spranger et al.; licensee BioMed Central Ltd.

【 图 表 】

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