Systemic antitumor immunity by PD-1/PD-L1 inhibition is potentiated by vascular-targeted photodynamic therapy of primary tumors Journal Article
| Authors: | O'Shaughnessy, M. J.; Murray, K. S.; La Rosa, S. P.; Budhu, S.; Merghoub, T.; Somma, A.; Monette, S.; Kim, K.; Corradi, R. B.; Scherz, A.; Coleman, J. A. |
| Article Title: | Systemic antitumor immunity by PD-1/PD-L1 inhibition is potentiated by vascular-targeted photodynamic therapy of primary tumors |
| Abstract: | Purpose: 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. Experimental Design: 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 and 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. Results: 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 CD8þ:regulatory T cell (Treg) and CD4þFoxP3-:Treg 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. Conclusions: 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. © 2017 American Association for Cancer Research. |
| Keywords: | controlled study; unclassified drug; nonhuman; antineoplastic agent; cd8+ t lymphocyte; tumor associated leukocyte; mouse; animal tissue; animal experiment; animal model; tumor regression; tumor xenograft; renal cell carcinoma; survival time; lung metastasis; regulatory t lymphocyte; cd4+ t lymphocyte; lymphocytic infiltration; photodynamic therapy; programmed death 1 ligand 1; programmed death 1 receptor; tumor microenvironment; tumor necrosis; programmed death 1 ligand 1 antibody; programmed death 1 antibody; male; priority journal; article; padeliporfin |
| Journal Title: | Clinical Cancer Research |
| Volume: | 24 |
| Issue: | 3 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2018-02-01 |
| Start Page: | 592 |
| End Page: | 599 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-17-0186 |
| PROVIDER: | scopus |
| PUBMED: | 28954788 |
| PMCID: | PMC7558370 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2018 -- Source: Scopus |
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