Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM

Dimitrios Mathios, Jennifer E. Kim, Antonella Mangraviti, Jillian Phallen, Chul Kee Park, Christopher M. Jackson, Tomas Garzon-Muvdi, Eileen Kim, Debebe Theodros, Magdalena Polanczyk, Allison M. Martin, Ian Suk, Xiaobu Ye, Betty Tyler, Chetan Bettegowda, Henry Brem, Drew M. Pardoll, Michael Lim

Research output: Contribution to journalArticlepeer-review

Abstract

The immunosuppressive effects of chemotherapy present a challenge for designing effective cancer immunotherapy strategies. We hypothesized that although systemic chemotherapy (SC) exhibits negative immunologic effects, local chemotherapy (LC) can potentiate an antitumor immuneresponse.We showthat LC combinedwith anti-programmed cell death protein 1 (PD-1) facilitates an antitumor immune response and improves survival (P < 0.001) in glioblastoma. LC-treated mice had increased infiltration of tumor-associated dendritic cells and clonal expansion of antigen-specific T effector cells. In comparison, SC resulted in systemic and intratumoral lymphodepletion, with decreased immune memory in long-term survivors. Furthermore, adoptive transfer of CD8+ cells from LC-treated mice partially rescued SC-treated mice after tumor rechallenge. Last, the timing of chemo-and immunotherapy had differential effects on anti-PD-1 efficacy. This study suggests that both mode of delivery and timing have distinct effects on the efficacy of anti-PD-1. The results of thiswork could help guide the selection and scheduling of combination treatment for patients with glioblastoma and other tumor types.

Original languageEnglish (US)
Article number370ra180
JournalScience Translational Medicine
Volume8
Issue number370
DOIs
StatePublished - Dec 21 2016

ASJC Scopus subject areas

  • Medicine(all)

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