A Senescence-mimicking (senomimetic) VEGFR TKI Side-effect Primes Tumor Immune Responses Via IFN/STING Signaling

Overview

Journal Mol Cancer Ther

Date 2024 May 1

PMID 38690835

Authors

Melissa Dolan

Yuhao Shi

Michalis Mastri

Mark D Long

Amber McKenery

James W Hill

Cristina Vaghi

Sebastien Benzekry

Joseph Barbi

John M L Ebos

Affiliations

Soon will be listed here.

Abstract

Tyrosine kinase inhibitors (TKIs) that block the vascular endothelial growth factor receptors (VEGFRs) disrupt tumor angiogenesis but also have many unexpected side-effects that impact tumor cells directly. This includes the induction of molecular markers associated with senescence, a form of cellular aging that typically involves growth arrest. We have shown that VEGFR TKIs can hijack these aging programs by transiently inducting senescence-markers (SMs) in tumor cells to activate senescence-associated secretory programs that fuel drug resistance. Here we show that these same senescence-mimicking ('senomimetic') VEGFR TKI effects drive an enhanced immunogenic signaling that, in turn, can alter tumor response to immunotherapy. Using a live-cell sorting method to detect beta-galactosidase, a commonly used SM, we found that subpopulations of SM-expressing (SM+) tumor cells have heightened interferon (IFN) signaling and increased expression of IFN-stimulated genes (ISGs). These ISG increases were under the control of the STimulator of INterferon Gene (STING) signaling pathway, which we found could be directly activated by several VEGFR TKIs. TKI-induced SM+ cells could stimulate or suppress CD8 T-cell activation depending on host:tumor cell contact while tumors grown from SM+ cells were more sensitive to PD-L1 inhibition in vivo, suggesting that offsetting immune-suppressive functions of SM+ cells can improve TKI efficacy overall. Our findings may explain why some (but not all) VEGFR TKIs improve outcomes when combined with immunotherapy and suggest that exploiting senomimetic drug side-effects may help identify TKIs that uniquely 'prime' tumors for enhanced sensitivity to PD-L1 targeted agents.

References

Ruscetti M, Leibold J, Bott M, Fennell M, Kulick A, Salgado N . NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination. Science. 2018; 362(6421):1416-1422. PMC: 6711172. DOI: 10.1126/science.aas9090. View

Mi H, Muruganujan A, Casagrande J, Thomas P . Large-scale gene function analysis with the PANTHER classification system. Nat Protoc. 2013; 8(8):1551-66. PMC: 6519453. DOI: 10.1038/nprot.2013.092. View

Tracz A, Mastri M, Lee C, Pili R, Ebos J . Modeling spontaneous metastatic renal cell carcinoma (mRCC) in mice following nephrectomy. J Vis Exp. 2014; (86). PMC: 4183115. DOI: 10.3791/51485. View

Duy C, Li M, Teater M, Meydan C, Garrett-Bakelman F, Lee T . Chemotherapy Induces Senescence-Like Resilient Cells Capable of Initiating AML Recurrence. Cancer Discov. 2021; 11(6):1542-1561. PMC: 8178167. DOI: 10.1158/2159-8290.CD-20-1375. View

Sistigu A, Yamazaki T, Vacchelli E, Chaba K, Enot D, Adam J . Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat Med. 2014; 20(11):1301-9. DOI: 10.1038/nm.3708. View

Choueiri T, Powles T, Burotto M, Escudier B, Bourlon M, Zurawski B . Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021; 384(9):829-841. PMC: 8436591. DOI: 10.1056/NEJMoa2026982. View

Ebos J, Lee C, Bogdanovic E, Alami J, van Slyke P, Francia G . Vascular endothelial growth factor-mediated decrease in plasma soluble vascular endothelial growth factor receptor-2 levels as a surrogate biomarker for tumor growth. Cancer Res. 2008; 68(2):521-9. DOI: 10.1158/0008-5472.CAN-07-3217. View

Debacq-Chainiaux F, Erusalimsky J, Campisi J, Toussaint O . Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc. 2009; 4(12):1798-806. DOI: 10.1038/nprot.2009.191. View

Wang L, Wang S, Li W . RSeQC: quality control of RNA-seq experiments. Bioinformatics. 2012; 28(16):2184-5. DOI: 10.1093/bioinformatics/bts356. View

10.

Bollard J, Miguela V, Ruiz de Galarreta M, Venkatesh A, Bian C, Roberto M . Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma. Gut. 2016; 66(7):1286-1296. PMC: 5512174. DOI: 10.1136/gutjnl-2016-312268. View

11.

Sharpless N, Sherr C . Forging a signature of in vivo senescence. Nat Rev Cancer. 2015; 15(7):397-408. DOI: 10.1038/nrc3960. View

12.

Hu Z, Yuan J, Long M, Jiang J, Zhang Y, Zhang T . The Cancer Surfaceome Atlas integrates genomic, functional and drug response data to identify actionable targets. Nat Cancer. 2022; 2(12):1406-1422. PMC: 9940627. DOI: 10.1038/s43018-021-00282-w. View

13.

Zhang L, Wei X, Wang Z, Liu P, Hou Y, Xu Y . NF-κB activation enhances STING signaling by altering microtubule-mediated STING trafficking. Cell Rep. 2023; 42(3):112185. DOI: 10.1016/j.celrep.2023.112185. View

14.

Gotink K, Broxterman H, Labots M, de Haas R, Dekker H, Honeywell R . Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance. Clin Cancer Res. 2011; 17(23):7337-46. PMC: 4461037. DOI: 10.1158/1078-0432.CCR-11-1667. View

15.

Coppe J, Desprez P, Krtolica A, Campisi J . The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010; 5:99-118. PMC: 4166495. DOI: 10.1146/annurev-pathol-121808-102144. View

16.

Velarde M, Demaria M . Targeting Senescent Cells: Possible Implications for Delaying Skin Aging: A Mini-Review. Gerontology. 2016; 62(5):513-8. DOI: 10.1159/000444877. View

17.

Bent E, Gilbert L, Hemann M . A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory responses. Genes Dev. 2016; 30(16):1811-21. PMC: 5024680. DOI: 10.1101/gad.284851.116. View

18.

Zhang H, Zoued A, Liu X, Sit B, Waldor M . Type I interferon remodels lysosome function and modifies intestinal epithelial defense. Proc Natl Acad Sci U S A. 2020; 117(47):29862-29871. PMC: 7703599. DOI: 10.1073/pnas.2010723117. View

19.

Diaz-Montero C, Mao F, Barnard J, Parker Y, Zamanian-Daryoush M, Pink J . MEK inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model. Br J Cancer. 2016; 115(8):920-928. PMC: 5061902. DOI: 10.1038/bjc.2016.263. View

20.

Davan-Wetton C, Pessolano E, Perretti M, Montero-Melendez T . Senescence under appraisal: hopes and challenges revisited. Cell Mol Life Sci. 2021; 78(7):3333-3354. PMC: 8038995. DOI: 10.1007/s00018-020-03746-x. View