In:
Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 8, No. 3_Supplement ( 2020-03-01), p. B89-B89
Abstract:
Introduction: Only a fraction of hepatocellular carcinoma (HCC) patients benefit from programmed death receptor-1 (PD-1) blockade. Combining PD-1 blockade with antiangiogenic treatments has been able to substantially increase the fraction of responsive HCC patients, but the mechanism of this interaction is unknown. We recapitulated these clinical outcomes (response vs. resistance) using orthotopic murine models of HCC. VEGFR2 blockade significantly delayed primary tumor growth but failed to prolong survival, while anti-PD-1 monotherapy conferred a minor survival. However, dual anti-PD-1/VEGFR-2 therapy significantly inhibited primary tumor growth and doubled survival in multiple models. Combination therapy reprogrammed the immune microenvironment by increasing CD8+ cytotoxic T-cell infiltration and activation, improving the ratio of anti- vs. pro-tumor-associated macrophages, and reducing T regulatory cell (Treg) infiltration in HCC tissue. Moreover, we found that VEGFR-2 blockade increased the PD-1 expression in tumor-infiltrating CD4+ cells. Under anti-PD-1 therapy, CD4+ cells promote normalized vessel formation in the face of antiangiogenic therapy. Conclusion: We show that dual anti-PD-1/VEGFR-2 therapy has a durable vessel fortification effect in HCC and can overcome treatment resistance to either treatment alone and increase survival in both anti-PD-1 therapy resistant and responsive HCC models. Citation Format: Meenal Datta, Kohei Shigeta, Tai Hato, Shuji Kitihara, Ivy X. Chen, Aya Matsui, Hiroto Kikuchi, Emilie Mamessier, Shuichi Aoki, Rakesh R. Ramjiawan, Hiroki Ochiai, Nabeel Bardeesy, Peigen Huang, Rakesh K. Jain, Mark Cobbold, Andrew X. Zhu, Dan G. Duda. Dual PD-1 and VEGFR-2 blockade induces vascular normalization and enhances antitumor immune responses in hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B89.
Type of Medium:
Online Resource
ISSN:
2326-6066
,
2326-6074
DOI:
10.1158/2326-6074.TUMIMM19-B89
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2020
detail.hit.zdb_id:
2732517-9
