Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy

被引：306

作者：

Jiao, Shiping ^{[1
,3
]}

Subudhi, Sumit K. ^{[1
]}

Aparicio, Ana ^{[1
]}

Ge, Zhongqi ^{[2
]}

Guan, Baoxiang ^{[1
]}

Miura, Yuji ^{[1
]}

Sharma, Padmanee ^{[1
,2
,3
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr UTHlth, Grad Sch Biomed Sci, Houston, TX 77030 USA

来源：

CELL | 2019年 / 179卷 / 05期

关键词：

IFN-GAMMA; TGF-BETA; COMBINED NIVOLUMAB; CELLS; CANCER; IPILIMUMAB; TH17; MEMORY; EFFECTOR; DIFFERENTIATION;

D O I：

10.1016/j.cell.2019.10.029

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Immune checkpoint therapy (ICT) shows encouraging results in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC) but still elicits a sub-optimal response among those with bone metastases. Analysis of patients' bone marrow samples revealed increased T(h)17 instead of T(h)1 subsets after ICT. To further evaluate the different tumor microenvironments, we injected mice with prostate tumor cells either subcutaneously or intraosseously. ICT in the subcutaneous CRPC model significantly increases intra-tumoral T(h)1 subsets and improves survival. However, ICT fails to elicit an anti-tumor response in the bone CRPC model despite an increase in the intra-tumoral CD4 T cells, which are polarized to T(h)17 rather than T(h)1 lineage. Mechanistically, tumors in the bone promote osteoclast-mediated bone resorption that releases TGF-8, which restrains T(h)1 lineage development. Blocking TGF-beta along with ICT increases T(h)1 subsets and promotes clonal expansion of CD8 T cells and subsequent regression of bone CRPC and improves survival.

引用

页码：1177 / +

页数：27

共 56 条

[11]

Dong HD, 2002, NAT MED, V8, P793, DOI 10.1038/nm730

[12] TGF-β induces Foxp3+T-regulatory cells from CD4+CD25-precursors [J].

Fu, S ;

Zhang, N ;

Yopp, AC ;

Chen, DM ;

Mao, MW ;

Chen, D ;

Zhang, HJ ;

Ding, YZ ;

Bromberg, JS .

AMERICAN JOURNAL OF TRANSPLANTATION, 2004, 4 (10) :1614-1627

[13] Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer Phase 2 Clinical KEYNOTE-059 Trial [J].

Fuchs, Charles S. ;

Doi, Toshihiko ;

Jang, Raymond W. ;

Muro, Kei ;

Satoh, Taroh ;

Machado, Manuela ;

Sun, Weijing ;

Jalal, Shadia I. ;

Shah, Manish A. ;

Metges, Jean-Phillipe ;

Garrido, Marcelo ;

Golan, Talia ;

Mandala, Mario ;

Wainberg, Zev A. ;

Catenacci, Daniel V. ;

Ohtsu, Atsushi ;

Shitara, Kohei ;

Geva, Ravit ;

Bleeker, Jonathan ;

Ko, Andrew H. ;

Ku, Geoffrey ;

Philip, Philip ;

Enzinger, Peter C. ;

Bang, Yung-Jue ;

Levitan, Diane ;

Wang, Jiangdian ;

Rosales, Minori ;

Dalal, Rita P. ;

Yoon, Harry H. .

JAMA ONCOLOGY, 2018, 4 (05)

[14] Type, density, and location of immune cells within human colorectal tumors predict clinical outcome [J].

Galon, Jerom ;

Costes, Anne ;

Sanchez-Cabo, Fatima ;

Kirilovsky, Amos ;

Mlecnik, Bernhard ;

Lagorce-Pages, Christine ;

Tosolini, Marie ;

Camus, Matthieu ;

Berger, Anne ;

Wind, Philippe ;

Zinzindohoue, Franck ;

Bruneval, Patrick ;

Cugnenc, Paul-Henri ;

Trajanoski, Zlatko ;

Fridman, Wolf-Herman ;

Pages, Franck .

SCIENCE, 2006, 313 (5795) :1960-1964

[15] VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer [J].

Gao, Jianjun ;

Ward, John F. ;

Pettaway, Curtis A. ;

Shi, Lewis Z. ;

Subudhi, Sumit K. ;

Vence, Luis M. ;

Zhao, Hao ;

Chen, Jianfeng ;

Chen, Hong ;

Efstathiou, Eleni ;

Troncoso, Patricia ;

Allison, James P. ;

Logothetis, Christopher J. ;

Wistuba, Ignacio I. ;

Sepulveda, Manuel A. ;

Sun, Jingjing ;

Wargo, Jennifer ;

Blando, Jorge ;

Sharma, Padmanee .

NATURE MEDICINE, 2017, 23 (05) :551-+

[16] Meta-Analysis Evaluating the Impact of Site of Metastasis on Overall Survival in Men With Castration-Resistant Prostate Cancer [J].

Halabi, Susan ;

Kelly, William Kevin ;

Ma, Hua ;

Zhou, Haojin ;

Solomon, Nicole C. ;

Fizazi, Karim ;

Tangen, Catherine M. ;

Rosenthal, Mark ;

Petrylak, Daniel P. ;

Hussain, Maha ;

Vogelzang, Nicholas J. ;

Thompson, Ian M. ;

Chi, Kim N. ;

de Bono, Johann ;

Armstrong, Andrew J. ;

Eisenberger, Mario A. ;

Fandi, Abderrahim ;

Li, Shaoyi ;

Araujo, John C. ;

Logothetis, Christopher J. ;

Quinn, David I. ;

Morris, Michael J. ;

Higano, Celestia S. ;

Tannock, Ian F. ;

Small, Eric J. .

JOURNAL OF CLINICAL ONCOLOGY, 2016, 34 (14) :1652-U191

[17] Distribution and Clinical Significance of Th17 Cells in the Tumor Microenvironment and Peripheral Blood of Pancreatic Cancer Patients [J].

He, Songbing ;

Fei, Min ;

Wu, Yugang ;

Zheng, Dingcheng ;

Wan, Daiwei ;

Wang, Liang ;

Li, Dechun .

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2011, 12 (11) :7424-7437

[18]

Hellmann MD, 2017, LANCET ONCOL, V18, P31, DOI [10.1016/S1470-2045(16)30624-6, 10.1016/s1470-2045(16)30624-6]

[19] Improved Survival with Ipilimumab in Patients with Metastatic Melanoma [J].

Hodi, F. Stephen ;

O'Day, Steven J. ;

McDermott, David F. ;

Weber, Robert W. ;

Sosman, Jeffrey A. ;

Haanen, John B. ;

Gonzalez, Rene ;

Robert, Caroline ;

Schadendorf, Dirk ;

Hassel, Jessica C. ;

Akerley, Wallace ;

van den Eertwegh, Alfons J. M. ;

Lutzky, Jose ;

Lorigan, Paul ;

Vaubel, Julia M. ;

Linette, Gerald P. ;

Hogg, David ;

Ottensmeier, Christian H. ;

Lebbe, Celeste ;

Peschel, Christian ;

Quirt, Ian ;

Clark, Joseph I. ;

Wolchok, Jedd D. ;

Weber, Jeffrey S. ;

Tian, Jason ;

Yellin, Michael J. ;

Nichol, Geoffrey M. ;

Hoos, Axel ;

Urba, Walter J. .

NEW ENGLAND JOURNAL OF MEDICINE, 2010, 363 (08) :711-723

[20] Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin [J].

Intlekofer, AM ;

Takemoto, N ;

Wherry, EJ ;

Longworth, SA ;

Northrup, JT ;

Palanivel, VR ;

Mullen, AC ;

Gasink, CR ;

Kaech, SM ;

Miller, JD ;

Gapin, L ;

Ryan, K ;

Russ, AP ;

Lindsten, T ;

Orange, JS ;

Goldrath, AW ;

Ahmed, R ;

Reiner, SL .

NATURE IMMUNOLOGY, 2005, 6 (12) :1236-1244

← 1 2 3 4 5 6 →