Antibody-mediated neutralization of soluble MIC significantly enhances CTLA4 blockade therapy

Jingyu Zhang, Dai Liu, Guangfu Li, Kevin F. Staveley-O'Carroll, Julie N. Graff, Zihai Li, Jennifer D. Wu

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Antibody therapy targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4) elicited survival benefits in cancer patients; however, the overall response rate is limited. In addition, anti-CTLA4 antibody therapy induces a high rate of immune-related adverse events. The underlying factors that may influence anti-CTLA4 antibody therapy are not well defined. We report the impact of a cancer-derived immune modulator, the human-soluble natural killer group 2D (NKG2D) ligand sMIC (solublemajor histocompatibility complex I chain-relatedmolecule), on the therapeutic outcome of anti-CTLA4 antibody using anMIC transgenic spontaneousTRAMP(transgenic adenocarcinomaof the mouse prostate)/ MIC tumor model. Unexpectedly, animals with elevated serum sMIC (sMIChi) responded poorly to anti-CTLA4 antibody therapy, with significantly shortened survival due to increased lung metastasis. These sMIChi animals also developed colitis in response to anti-CTLA4 antibody therapy. Coadministration of an sMIC-neutralizing monoclonal antibody with the anti-CTLA4 antibody alleviated treatment-induced colitis in sMIChi animals and generated a cooperative antitumor therapeutic effect by synergistically augmenting innate and adoptive antitumor immune responses. Our findings imply that a new combination therapy could improve the clinical response to anti-CTLA4 antibody therapy. Our findings also suggest that prescreening cancer patients for serum sMIC may help in selecting candidates who will elicit a better response to anti-CTLA4 antibody therapy.

Original languageEnglish (US)
Article numbere1602133
JournalScience Advances
Volume3
Issue number5
DOIs
StatePublished - May 2017

ASJC Scopus subject areas

  • General

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