Combined PD-L1/TGFβ blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors

被引:39
作者
Castiglioni, Alessandra [1 ]
Yang, Yagai [1 ]
Williams, Katherine [1 ]
Gogineni, Alvin [1 ]
Lane, Ryan S. [1 ]
Wang, Amber W. [1 ]
Shyer, Justin A. [1 ]
Zhang, Zhe [1 ]
Mittman, Stephanie [1 ]
Gutierrez, Alan [1 ]
Astarita, Jillian L. [1 ]
Thai, Minh [1 ]
Hung, Jeffrey [1 ]
Yang, Yeqing Angela [1 ]
Pourmohamad, Tony [1 ]
Himmels, Patricia [1 ]
De Simone, Marco [1 ]
Elstrott, Justin [1 ]
Capietto, Aude-Helene [1 ]
Cubas, Rafael [1 ]
Modrusan, Zora [1 ]
Sandoval, Wendy [1 ]
Ziai, James [1 ]
Gould, Stephen E. [1 ]
Fu, Wenxian [1 ]
Wang, Yulei [1 ]
Koerber, James T. [1 ]
Sanjabi, Shomyseh [1 ]
Mellman, Ira [1 ]
Turley, Shannon J. [1 ]
Mueller, Soeren [1 ]
机构
[1] Genentech Inc, South San Francisco, CA 94080 USA
关键词
MOLECULAR SIGNATURE; CHECKPOINT BLOCKADE; CLINICAL-RESPONSE; SUBSETS; TRANSCRIPTION; PERSISTENCE; ACTIVATION; EXHAUSTION; EXPRESSION; TGF-BETA-1;
D O I
10.1038/s41467-023-40398-4
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
It has been previously shown that combining immune checkpoint inhibitors with TGF & beta; blockade potentiates anti-tumor immune responses. Here the authors show that, in an immune excluded preclinical tumor model, combining therapeutic anti-PD-L1 with anti-TGF & beta; treatment promotes expansion and differentiation of stem-cell like CD8 + T cells. TGF & beta; signaling is associated with non-response to immune checkpoint blockade in patients with advanced cancers, particularly in the immune-excluded phenotype. While previous work demonstrates that converting tumors from excluded to inflamed phenotypes requires attenuation of PD-L1 and TGF & beta; signaling, the underlying cellular mechanisms remain unclear. Here, we show that TGF & beta; and PD-L1 restrain intratumoral stem cell-like CD8 T cell (T-SCL) expansion and replacement of progenitor-exhausted and dysfunctional CD8 T cells with non-exhausted T effector cells in the EMT6 tumor model in female mice. Upon combined TGF & beta;/PD-L1 blockade IFN & gamma;(hi) CD8 T effector cells show enhanced motility and accumulate in the tumor. Ensuing IFN & gamma; signaling transforms myeloid, stromal, and tumor niches to yield an immune-supportive ecosystem. Blocking IFN & gamma; abolishes the anti-PD-L1/anti-TGF & beta; therapy efficacy. Our data suggest that TGF & beta; works with PD-L1 to prevent T-SCL expansion and replacement of exhausted CD8 T cells, thereby maintaining the T cell compartment in a dysfunctional state.
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页数:19
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