PD-1/PD-L1 pathway inhibition is effective against advanced renal cell carcinoma, although results are variable and may depend on host factors including the tumor microenvironment. Vascular-targeted photodynamic (VTP) therapy with the photosensitizer WST11 induces a defined local immune response, and we sought to determine whether this could potentiate the local and systemic antitumor response to PD-1 pathway inhibition.
Using an orthotopic Renca murine model of renal cell carcinoma that develops lung metastases, we treated primary renal tumors with either VTP alone, PD-1/PD-L1 antagonistic antibodies alone, or a combination of VTP and antibodies, then examined treatment responses including immune infiltration in primary and metastatic sites. Modulation of PD-L1 expression by VTP in human xenograft tumors was also assessed.
Treatment of renal tumors with VTP in combination with systemic PD-1/PD-L1 pathway inhibition, but neither treatment alone, resulted in regression of primary tumors, prevented growth of lung metastases and prolonged survival in a preclinical mouse model. Analysis of tumor-infiltrating lymphocytes revealed that treatment effect was associated with increased CD8+:regulatory T cell and CD4+FoxP3-:regulatory T cell ratios in primary renal tumors and increased T cell infiltration in sites of lung metastasis. Furthermore, PD-L1 expression is induced following VTP treatment of human renal cell carcinoma xenografts.
Our results demonstrate a role for local immune modulation with VTP in combination with PD-1/PD-L1 pathway inhibition for generation of potent local and systemic antitumor responses. This combined-modality strategy may be an effective therapy in cancers resistant to PD-1/PD-L1 pathway inhibition alone.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2017 Sep 27 [Epub ahead of print]
Matthew J O'Shaughnessy, Katie S Murray, Stephen P La Rosa, Sadna Budhu, Taha Merghoub, Alexander Somma, Sebastien Monette, Kwanghee Kim, Renato Beluco Corradi, Avigdor Scherz, Jonathan Coleman
Urology Service, Memorial Sloan Kettering Cancer Center ., Urology Service, University of Missouri., Memorial Sloan Kettering Cancer Center., Immunology, Memorial Sloan-Kettering Cancer Center., Tri-Institutional Laboratory of Comparative Pathology, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, and The Rockefeller University, Memorial Sloan Kettering Cancer Center., Surgery, Memorial Sloan Kettering Cancer Center., Weizmann Institute of Science., Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center.