BCAT2 Shapes a Noninflamed Tumor Microenvironment and Induces Resistance to Anti-PD-1/PD-L1 Immunotherapy by Negatively Regulating Proinflammatory Chemokines and Anticancer Immunity

Zhiyong Cai; Jinbo Chen; Zhengzheng Yu; Huihuang Li; Zhi Liu; Dingshan Deng; Jinhui Liu; Chunliang Chen; Chunyu Zhang; Zhenyu Ou; Minfeng Chen; Jiao Hu; Xiongbing Zu

doi:10.1002/advs.202207155

BCAT2 Shapes a Noninflamed Tumor Microenvironment and Induces Resistance to Anti-PD-1/PD-L1 Immunotherapy by Negatively Regulating Proinflammatory Chemokines and Anticancer Immunity

Adv Sci (Weinh). 2023 Mar;10(8):e2207155. doi: 10.1002/advs.202207155. Epub 2023 Jan 15.

Authors

Zhiyong Cai^{1

2}, Jinbo Chen^{1

2}, Zhengzheng Yu^{2

3}, Huihuang Li^{1

2}, Zhi Liu^{1

2}, Dingshan Deng^{1

2}, Jinhui Liu^{1

2}, Chunliang Chen^{1

2}, Chunyu Zhang^{1

2}, Zhenyu Ou^{1

2}, Minfeng Chen^{1

2}, Jiao Hu^{1

2}, Xiongbing Zu^{1

2}

Affiliations

¹ Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China.
² National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China.
³ Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China.

Abstract

To improve response rate of monotherapy of immune checkpoint blockade (ICB), it is necessary to find an emerging target in combination therapy. Through analyzing tumor microenvironment (TME)-related indicators, it is validated that BCAT2 shapes a noninflamed TME in bladder cancer. The outcomes of multiomics indicate that BCAT2 has an inhibitory effect on cytotoxic lymphocyte recruitment by restraining activities of proinflammatory cytokine/chemokine-related pathways and T-cell-chemotaxis pathway. Immunoassays reveal that secretion of CD8⁺ T-cell-related chemokines keeps a robust negative correlation with BCAT2, generating a decreasing tendency of CD8⁺ T cells around BCAT2⁺ tumor cells from far to near. Cotreatment of BCAT2 deficiency and anti-PD-1 antibody has a synergistic effect in vivo, implying the potential of BCAT2 in combination therapy. Moreover, the value of BCAT2 in predicting efficacy of immunotherapy is validated in multiple immunotherapy cohorts. Together, as a key molecule in TME, BCAT2 is an emerging target in combination with ICB and a biomarker of guiding precision therapy.

Keywords: immunotherapy; molecular subtype; precision therapy; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

B7-H1 Antigen* / metabolism
B7-H1 Antigen* / therapeutic use
CD8-Positive T-Lymphocytes
Chemokines / metabolism
Immune Checkpoint Inhibitors* / metabolism
Immune Checkpoint Inhibitors* / pharmacology
Immunotherapy*
Tumor Microenvironment* / genetics
Tumor Microenvironment* / immunology

Substances

B7-H1 Antigen
Chemokines
BCAT2 protein, human
Immune Checkpoint Inhibitors

Abstract

Publication types

MeSH terms

Substances

Grants and funding