Selective targeting of GARP-LTGFβ axis in the tumor microenvironment augments PD-1 blockade via enhancing CD8+ T cell antitumor immunity

被引：20

作者：

Li, Anqi ^{[1
,2
,3
]}

Chang, Yuzhou ^{[2
,3
,4
]}

Song, No-Joon ^{[2
,3
]}

Wu, Xingjun ^{[2
,3
]}

Chung, Dongjun ^{[2
,3
,4
]}

Riesenberg, Brian P. ^{[2
,3
]}

Velegraki, Maria ^{[2
,3
]}

Giuliani, Giuseppe D. ^{[5
,6
]}

Das, Komal ^{[2
,3
]}

Okimoto, Tamio ^{[1
]}

Kwon, Hyunwoo ^{[1
,2
,3
]}

Chakravarthy, Karthik B. ^{[1
,2
,3
]}

Bolyard, Chelsea ^{[2
,3
]}

Wang, Yi ^{[2
,3
]}

He, Kai ^{[2
,3
,7
]}

Gatti-Mays, Margaret ^{[2
,3
,7
]}

Das, Jayajit ^{[2
,3
,8
]}

Yang, Yiping ^{[2
,3
,9
]}

Gewirth, Daniel T. ^{[10
]}

Ma, Qin ^{[2
,3
,4
]}

Carbone, David ^{[2
,3
,7
]}

Li, Zihai ^{[2
,3
,7
]}

机构：

[1] Ohio State Univ, Coll Med, Columbus, OH 43210 USA

[2] Ohio State Univ, Comprehens Canc Ctr, Pelotonia Inst Immunooncol, Arthur G James Canc Hosp, Columbus, OH 43210 USA

[3] Ohio State Univ, Richard J Solove Res Inst, Columbus, OH 43210 USA

[4] Ohio State Univ, Coll Med, Dept Biomed Informat, Columbus, OH 43210 USA

[5] Nationwide Childrens Hosp, Battelle Ctr Math Med, Abigail Wexner Res Inst, Columbus, OH USA

[6] Ohio State Univ, Dept Phys, 174 W 18th Ave, Columbus, OH 43210 USA

[7] Ohio State Univ, Div Med Oncol, Dept Internal Med, Coll Med, Columbus, OH 43210 USA

[8] Ohio State Univ, Coll Med, Dept Pediat, Columbus, OH 43210 USA

[9] Ohio State Univ, Coll Med, Div Hematol, Columbus, OH 43210 USA

[10] Hauptman Woodward Med Res Inst, New York, NY USA

来源：

JOURNAL FOR IMMUNOTHERAPY OF CANCER | 2022年 / 10卷 / 09期

关键词：

immunotherapy; CD8-positive T-lymphocytes; programmed cell death 1 receptor; transplantation immunology; TGF-BETA; EXPRESSION; TGF-BETA-1; RECEPTOR; TOLERANCE;

D O I：

10.1136/jitc-2022-005433

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background Immune checkpoint blockade (ICB) has revolutionized cancer immunotherapy. However, most patients with cancer fail to respond clinically. One potential reason is the accumulation of immunosuppressive transforming growth factor beta (TGF beta) in the tumor microenvironment (TME). TGF beta drives cancer immune evasion in part by inducing regulatory T cells (Tregs) and limiting CD8(+) T cell function. Glycoprotein-A repetitions predominant (GARP) is a cell surface docking receptor for activating latent TGF beta 1, TGF beta 2 and TGF beta 3, with its expression restricted predominantly to effector Tregs, cancer cells, and platelets. Methods We investigated the role of GARP in human patients with cancer by analyzing existing large databases. In addition, we generated and humanized an anti-GARP monoclonal antibody and evaluated its antitumor efficacy and underlying mechanisms of action in murine models of cancer. Results We demonstrate that GARP overexpression in human cancers correlates with a tolerogenic TME and poor clinical response to ICB, suggesting GARP blockade may improve cancer immunotherapy. We report on a unique anti-human GARP antibody (named PIIO-1) that specifically binds the ligand-interacting domain of all latent TGF beta isoforms. PIIO-1 lacks recognition of GARP-TGF beta complex on platelets. Using human LRRC32 (encoding GARP) knock-in mice, we find that PIIO-1 does not cause thrombocytopenia; is preferentially distributed in the TME; and exhibits therapeutic efficacy against GARP(+) and GARP(-) cancers, alone or in combination with anti-PD-1 antibody. Mechanistically, PIIO-1 treatment reduces canonical TGF beta signaling in tumor-infiltrating immune cells, prevents T cell exhaustion, and enhances CD8(+) T cell migration into the TME in a C-X-C motif chemokine receptor 3 (CXCR3)-dependent manner. Conclusion GARP contributes to multiple aspects of immune resistance in cancer. Anti-human GARP antibody PIIO-1 is an efficacious and safe strategy to block GARP-mediated LTGF beta activation, enhance CD8(+) T cell trafficking and functionality in the tumor, and overcome primary resistance to anti-PD-1 ICB. PIIO-1 therefore warrants clinical development as a novel cancer immunotherapeutic.

引用

页数：14