Beyond the Barrier: Unraveling the Mechanisms of Immunotherapy Resistance

被引：19

作者：

Bell, Hannah N. ^{[1
,2
,3
]}

Zou, Weiping ^{[1
,2
,3
,4
]}

机构：

[1] Univ Michigan, Dept Surg, Med Sch, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Ctr Excellence Canc Immunol & Immunotherapy, Rogel Canc Ctr, Med Sch, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Grad Programs Canc Biol & Immunol, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Dept Pathol, Med Sch, Ann Arbor, MI USA

来源：

ANNUAL REVIEW OF IMMUNOLOGY | 2024年 / 42卷

基金：

美国国家卫生研究院;

关键词：

immune checkpoint blockade; tumor microenvironment; immunotherapy resistance; PD-1; PD-L1; CTLA-4; T cell; REGULATORY T-CELLS; IMMUNE CHECKPOINT BLOCKADE; CANCER-IMMUNOTHERAPY; PD-1; BLOCKADE; TUMOR MICROENVIRONMENT; SOLID TUMORS; DOUBLE-BLIND; LUNG-CANCER; COMBINATION IMMUNOTHERAPY; ACQUIRED-RESISTANCE;

D O I：

10.1146/annurev-immunol-101819-024752

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Immune checkpoint blockade (ICB) induces a remarkable and durable response in a subset of cancer patients. However, most patients exhibit either primary or acquired resistance to ICB. This resistance arises from a complex interplay of diverse dynamic mechanisms within the tumor microenvironment (TME). These mechanisms include genetic, epigenetic, and metabolic alterations that prevent T cell trafficking to the tumor site, induce immune cell dysfunction, interfere with antigen presentation, drive heightened expression of coinhibitory molecules, and promote tumor survival after immune attack. The TME worsens ICB resistance through the formation of immunosuppressive networks via immune inhibition, regulatory metabolites, and abnormal resource consumption. Finally, patient lifestyle factors, including obesity and microbiome composition, influence ICB resistance. Understanding the heterogeneity of cellular, molecular, and environmental factors contributing to ICB resistance is crucial to develop targeted therapeutic interventions that enhance the clinical response. This comprehensive overview highlights key mechanisms of ICB resistance that may be clinically translatable.

引用

页码：521 / 550

页数：30

共 207 条

[21] Immunotherapy for Merkel cell carcinoma: a turning point in patient care [J].

Chan, Isaac S. ;

Bhatia, Shailender ;

Kaufman, Howard L. ;

Lipson, Evan J. .

JOURNAL FOR IMMUNOTHERAPY OF CANCER, 2018, 6

[22] Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression [J].

Chang, Chih-Hao ;

Qiu, Jing ;

O'Sullivan, David ;

Buck, Michael D. ;

Noguchi, Takuro ;

Curtis, Jonathan D. ;

Chen, Qiongyu ;

Gindin, Mariel ;

Gubin, Matthew M. ;

van der Windt, Gerritje J. W. ;

Tonc, Elena ;

Schreiber, Robert D. ;

Pearce, Edward J. ;

Pearce, Erika L. .

CELL, 2015, 162 (06) :1229-1241

[23] ARC-7: A phase II study to evaluate the safety and efficacy of zimberelimab alone, AB154 in combination with zimberelimab, and AB154 in combination with zimberelimab and AB928 in front-line, PD-L1 expressing, non-small cell lung cancer (NSCLC) [J].

Chaudhry, A. ;

Johnson, M. ;

Colburn, D. ;

Gilbert, H. ;

Garofalo, A. ;

Paoloni, M. ;

Krishnan, K. .

ANNALS OF ONCOLOGY, 2020, 31 :S897-S897

[24] Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response [J].

Chen, Gang ;

Huang, Alexander C. ;

Zhang, Wei ;

Zhang, Gao ;

Wu, Min ;

Xu, Wei ;

Yu, Zili ;

Yang, Jiegang ;

Wang, Beike ;

Sun, Honghong ;

Xia, Houfu ;

Man, Qiwen ;

Zhong, Wenqun ;

Antelo, Leonardo F. ;

Wu, Bin ;

Xiong, Xuepeng ;

Liu, Xiaoming ;

Guan, Lei ;

Li, Ting ;

Liu, Shujing ;

Yang, Ruifeng ;

Lu, Youtao ;

Dong, Liyun ;

McGettigan, Suzanne ;

Somasundaram, Rajasekharan ;

Radhakrishnan, Ravi ;

Mills, Gordon ;

Lu, Yiling ;

Kim, Junhyong ;

Chen, Youhai H. ;

Dong, Haidong ;

Zhao, Yifang ;

Karakousis, Giorgos C. ;

Mitchell, Tara C. ;

Schuchter, Lynn M. ;

Herlyn, Meenhard ;

Wherry, E. John ;

Xu, Xiaowei ;

Guo, Wei .

NATURE, 2018, 560 (7718) :382-+

[25] Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade [J].

Chen, Pei-Ling ;

Roh, Whijae ;

Reuben, Alexandre ;

Cooper, Zachary A. ;

Spencer, Christine N. ;

Prieto, Peter A. ;

Miller, John P. ;

Bassett, Roland L. ;

Gopalakrishnan, Vancheswaran ;

Wani, Khalida ;

De Macedo, Mariana Petaccia ;

Austin-Breneman, Jacob L. ;

Jiang, Hong ;

Chang, Qing ;

Reddy, Sangeetha M. ;

Chen, Wei-Shen ;

Tetzlaff, Michael T. ;

Broaddus, Russell J. ;

Davies, Michael A. ;

Gershenwald, Jeffrey E. ;

Haydu, Lauren ;

Lazar, Alexander J. ;

Patel, Sapna P. ;

Hwu, Patrick ;

Hwu, Wen-Jen ;

Diab, Adi ;

Glitza, Isabella C. ;

Woodman, Scott E. ;

Vence, Luis M. ;

Wistuba, Ignacio I. ;

Amaria, Rodabe N. ;

Kwong, Lawrence N. ;

Prieto, Victor ;

Davis, R. Eric ;

Ma, Wencai ;

Overwijk, Willem W. ;

Sharpe, Arlene H. ;

Hu, Jianhua ;

Futreal, P. Andrew ;

Blando, Jorge ;

Sharma, Padmanee ;

Allison, James P. ;

Chin, Lynda ;

Wargo, Jennifer A. .

CANCER DISCOVERY, 2016, 6 (08) :827-837

[26] Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition [J].

Cherkassky, Leonid ;

Morello, Aurore ;

Villena-Vargas, Jonathan ;

Feng, Yang ;

Dimitrov, Dimiter S. ;

Jones, David R. ;

Sadelain, Michel ;

Adusumilli, Prasad S. .

JOURNAL OF CLINICAL INVESTIGATION, 2016, 126 (08) :3130-3144

[27] Melanoma Brain Metastasis Pseudoprogression after Pembrolizumab Treatment [J].

Cohen, Justine V. ;

Alomari, Ahmed K. ;

Vortmeyer, Alexander O. ;

Jilaveanu, Lucia B. ;

Goldberg, Sarah B. ;

Mahajan, Amit ;

Chiang, Veronica L. ;

Kluger, Harriet M. .

CANCER IMMUNOLOGY RESEARCH, 2016, 4 (03) :179-182

[28] Lactate modulates CD4+ T-cell polarization and induces an immunosuppressive environment, which sustains prostate carcinoma progression via TLR8/miR21 axis [J].

Comito, G. ;

Iscaro, A. ;

Bacci, M. ;

Morandi, A. ;

Ippolito, L. ;

Parri, M. ;

Montagnani, I. ;

Raspollini, M. R. ;

Serni, S. ;

Simeoni, L. ;

Giannoni, E. ;

Chiarugi, P. .

ONCOGENE, 2019, 38 (19) :3681-3695

[29] Cancer immunotherapy efficacy and patients' sex: a systematic review and meta-analysis [J].

Conforti, Fabio ;

Pala, Laura ;

Bagnardi, Vincenzo ;

De Pas, Tommaso ;

Martinetti, Marco ;

Viale, Giuseppe ;

Gelber, Richard D. ;

Goldhirsch, Aron .

LANCET ONCOLOGY, 2018, 19 (06) :737-746

[30]

Cortes J, 2020, LANCET, V396, P1817, DOI 10.1016/S0140-6736(20)32531-9

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