Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade

被引：273

作者：

Andrews, Miles C. ^{[1
,2
,3
,4
]}

Duong, Connie P. M. ^{[5
,6
,7
]}

Gopalakrishnan, Vancheswaran ^{[1
]}

Iebba, Valerio ^{[5
,6
]}

Chen, Wei-Shen ^{[8
,9
]}

Derosa, Lisa ^{[5
,6
,7
]}

Khan, Md Abdul Wadud ^{[1
]}

Cogdill, Alexandria P. ^{[5
,6
,7
,8
]}

White, Michael G. ^{[1
]}

Wong, Matthew C. ^{[8
]}

Ferrere, Gladys ^{[5
,6
,7
]}

Fluckiger, Aurelie ^{[5
,6
,7
]}

Roberti, Maria P. ^{[5
,6
,7
]}

Opolon, Paule ^{[5
]}

Alou, Maryam Tidjani ^{[5
,6
,7
]}

Yonekura, Satoru ^{[5
,6
,7
]}

Roh, Whijae ^{[8
]}

Spencer, Christine N. ^{[10
]}

Curbelo, Irina Fernandez ^{[11
]}

Vence, Luis ^{[11
]}

Reuben, Alexandre ^{[12
]}

Johnson, Sarah ^{[1
]}

Arora, Reetakshi ^{[1
]}

Morad, Golnaz ^{[1
]}

Lastrapes, Matthew ^{[13
]}

Baruch, Erez N. ^{[8
]}

Little, Latasha ^{[8
]}

Gumbs, Curtis ^{[8
]}

Cooper, Zachary A. ^{[14
]}

Prieto, Peter A. ^{[15
]}

Wani, Khalida ^{[16
]}

Lazar, Alexander J. ^{[8
,16
]}

Tetzlaff, Michael T. ^{[16
]}

Hudgens, Courtney W. ^{[16
]}

Callahan, Margaret K. ^{[10
,17
]}

Adamow, Matthew ^{[17
,18
]}

Postow, Michael A. ^{[17
,18
]}

Ariyan, Charlotte E. ^{[19
]}

Gaudreau, Pierre-Olivier ^{[1
]}

Nezi, Luigi ^{[20
]}

Raoult, Didier ^{[21
]}

Mihalcioiu, Catalin ^{[22
]}

Elkrief, Arielle ^{[23
]}

Pezo, Rossanna C. ^{[24
]}

Haydu, Lauren E. ^{[1
]}

Simon, Julie M. ^{[1
]}

Tawbi, Hussein A. ^{[25
]}

McQuade, Jennifer ^{[25
]}

Hwu, Patrick ^{[25
]}

Hwu, Wen-Jen ^{[25
]}

机构：

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

[2] Olivia Newton John Canc Res Inst, Heidelberg, Vic, Australia

[3] La Trobe Univ, Sch Canc Med, Heidelberg, Vic, Australia

[4] Monash Univ, Deparment Med, Melbourne, Vic, Australia

[5] Gustave Roussy Canc Campus GRCC, Villejuif, France

[6] Inst Natl Sante & Rech Med INSERM U1015, Equipe Labellisee Ligue Natl Canc, Villejuif, France

[7] Univ Paris Saclay, Fac Med Kremlin Bicetre, Le Kremlin Bicetre, France

[8] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[9] Univ S Florida, Dept Dermatol, Morsani Coll Med, Tampa, FL 33620 USA

[10] Parker Inst Canc Immunotherapy, Dept Informat, San Francisco, CA USA

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

[12] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA

[13] Univ Texas Hlth, MD Anderson Canc Ctr, Grad Sch Biomed Sci GSBS, Houston, TX USA

[14] AstraZeneca, Gaithersburg, MD USA

[15] Univ Rochester, Med Ctr, Dept Surg, Rochester, NY 14642 USA

[16] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[17] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

[18] Mem Sloan Kettering Canc Ctr, Div Immunol, 1275 York Ave, New York, NY 10021 USA

[19] Mem Sloan Kettering Canc Ctr, Dept Surg, 1275 York Ave, New York, NY 10021 USA

[20] Ist Europeo Oncol, Milan, Italy

[21] Aix Marseille Univ, IHU Mediterranee Infect, MEPHI, IRD, Marseille, France

[22] McGill Univ, Fac Med & Hlth Sci, Dept Med, Hlth Ctr, Montreal, PQ, Canada

[23] McGill Univ, Cedars Canc Ctr, Hlth Ctr, Montreal, PQ, Canada

[24] Univ Toronto, Sunnybrook Odette Canc Ctr, Div Med Oncol, Toronto, ON, Canada

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

[26] Baylor Coll Med, Dept Virol & Microbiol, Houston, TX 77030 USA

来源：

NATURE MEDICINE | 2021年 / 27卷 / 08期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

BACTEROIDES-FRAGILIS GROUP; MELANOMA; IPILIMUMAB; NIVOLUMAB; RESISTANCE; EFFICACY; MECHANISMS; SEQUENCES; SURVIVAL; THERAPY;

D O I：

10.1038/s41591-021-01406-6

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：

Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any >= grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1 beta in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB. Clinical benefit or intestinal toxicity resulting from combined immune checkpoint blockade in patients with melanoma associates with prevalent commensal bacteria and can be decoupled by IL-1R inhibition.

引用

页码：1432 / +

页数：27

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