Senescence Inflames the Pancreatic Tumor Microenvironment
Authors: Giulia Petroni, Lorenzo Galluzzi
Journal: Cell Reports Medicine (2020)

Pancreatic adenocarcinomas (PDACs) are scarcely vascularized and thus virtually insensitive to chemotherapy and immunotherapy. In a recent issue of Cell, Lowe and collaborators1Ruscetti M. Morris J.P.t. Mezzadra R. Russell J. Leibold J. Romesser P.B. Simon J. Kulick A. Ho Y.J. Fennell M. et al.Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer.Cell. 2020; 181: 424-441Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar have demonstrated that senescence induction by MEK plus CDK4/CDK6 inhibitors favors PDAC revascularization coupled to infiltration by therapeutically actionable CD8+ T cells. Pancreatic adenocarcinomas (PDACs) are scarcely vascularized and thus virtually insensitive to chemotherapy and immunotherapy. In a recent issue of Cell, Lowe and collaborators1Ruscetti M. Morris J.P.t. Mezzadra R. Russell J. Leibold J. Romesser P.B. Simon J. Kulick A. Ho Y.J. Fennell M. et al.Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer.Cell. 2020; 181: 424-441Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar have demonstrated that senescence induction by MEK plus CDK4/CDK6 inhibitors favors PDAC revascularization coupled to infiltration by therapeutically actionable CD8+ T cells. Pancreatic adenocarcinomas (PDACs) are aggressive tumors with exceptionally dismal prognosis, at least in part owing to the robust stromal reaction that generally accompanies pancreatic oncogenesis. Indeed, growing PDACs establish a densely fibrotic and poorly vascularized tumor microenvironment (TME) that supports disease progression and resistance to treatment by limiting access to immune cells and chemotherapeutics.2Schnittert J. Bansal R. Prakash J. Targeting Pancreatic Stellate Cells in Cancer.Trends Cancer. 2019; 5: 128-142Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Genetic alterations common in human PDACs, including activating mutations of KRAS proto-oncogene, GTPase (KRAS), and loss-of-functions mutations in tumor protein p53 (TP53), have been mechanistically linked to pancreatic oncogenesis amidst an intricate paracrine network that co-opt pancreatic stellate cells (PSCs) to drive fibrosis and local immunosuppression.3Collins M.A. Bednar F. Zhang Y. Brisset J.C. Galbán S. Galbán C.J. Rakshit S. Flannagan K.S. Adsay N.V. Pasca di Magliano M. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice.J. Clin. Invest. 2012; 122: 639-653Crossref PubMed Scopus (421) Google Scholar Such a stromal component has attracted attention as a potential target for the development of novel treatments.2Schnittert J. Bansal R. Prakash J. Targeting Pancreatic Stellate Cells in Cancer.Trends Cancer. 2019; 5: 128-142Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar However, no therapies targeting components of the pancreatic TME have been approved for use in patients with PDAC so far. Lowe and collaborators have recently demonstrated that the TME of PDACs undergoing cellular senescence4Gorgoulis V. Adams P.D. Alimonti A. Bennett D.C. Bischof O. Bishop C. Campisi J. Collado M. Evangelou K. Ferbeyre G. et al.Cellular Senescence: Defining a Path Forward.Cell. 2019; 179: 813-827Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar in response to trametinib, an inhibitor of mitogen-activated protein kinase kinase 7 (MAP2K7, best known as MEK), plus palbociclib, a cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitor, supports an angiogenic response that enables the recruitment of therapeutically actionable CD8+ cytotoxic T lymphocytes (CTLs) (Figure 1).1Ruscetti M. Morris J.P.t. Mezzadra R. Russell J. Leibold J. Romesser P.B. Simon J. Kulick A. Ho Y.J. Fennell M. et al.Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer.Cell. 2020; 181: 424-441Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Lowe and colleagues set to investigate the efficacy of trametinib plus palbociclib (T/P) in vivo, in immunocompetent mouse models of PDACs driven by Kras and Trp53 (the mouse ortholog of human TP53) mutations. At odds with previous findings in models of KRAS-driven lung carcinomas,5Ruscetti M. Leibold J. Bott M.J. Fennell M. Kulick A. Salgado N.R. Chen C.C. Ho Y.J. Sanchez-Rivera F.J. Feucht J. et al.NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination.Science. 2018; 362: 1416-1422Crossref PubMed Scopus (95) Google Scholar T/P had limited therapeutic efficacy as it failed to recruit natural killer (NK) cells. Instead, T/P administration favored the generation of CD31+ blood (but not lymphatic) vessels harboring open lumens coupled to a reduction in stromal hyaluronic acid. This vascularization response was preserved in immunodeficient mice and depended on the secretion of pro-angiogenic factors including vascular endothelial growth factor A (VEGFA) by PDAC cells responding to T/P with a permanent proliferative arrest known as cellular senescence.4Gorgoulis V. Adams P.D. Alimonti A. Bennett D.C. Bischof O. Bishop C. Campisi J. Collado M. Evangelou K. Ferbeyre G. et al.Cellular Senescence: Defining a Path Forward.Cell. 2019; 179: 813-827Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar Such a senescence-associated secretory phenotype (SASP) originated from NF-κB signaling in PDAC cells, as demonstrated with a short-hairpin RNA (shRNA) targeting RELA proto-oncogene, NF-kB subunit (RELA, best known as p65). Vascularization depended on VEGFA signaling in endothelial cells (ECs) via kinase insert domain receptor (KDR), as shown with the KDR-specific antibody DC101. Conversely, EC activation linked to expression of markers such as intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) was mainly driven by interleukin 6 (IL6), C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand 1 (CXCL1).1Ruscetti M. Morris J.P.t. Mezzadra R. Russell J. Leibold J. Romesser P.B. Simon J. Kulick A. Ho Y.J. Fennell M. et al.Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer.Cell. 2020; 181: 424-441Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar T/P pre-administration improved the delivery of gemcitabine (a common chemotherapeutic) to mouse PDACs, an effect that (1) relied on KDR-mediated vascularization, (2) extended the survival of immunocompetent PDAC-bearing mice, and (3) could be recapitulated in immunodeficient mice bearing human PDAC xenografts. Depletion experiments confirmed that NK cells are not involved in the partial therapeutic efficacy of T/P in immunocompetent mice. Moreover, no differences were detected in the abundance of tumor-infiltrating neutrophils, myeloid-derived suppressor cells (MDSCs), and immunosuppressive CD4+CD25+FOXP3+ regulatory T (TREG) cells. Conversely, T/P-treated PDACs efficiently recruited CD8+ CTLs downstream of NF-κB signaling in PDAC cells, KDR-dependent vascularization, and VCAM1 expression by ECs. Supporting some degree of direct immunostimulation,6Petroni G. Formenti S.C. Chen-Kiang S. Galluzzi L. Immunomodulation by anticancer cell cycle inhibitors.Nat. Rev. Immunol. 2020; https://doi.org/10.1038/s41577-020-0300-yCrossref PubMed Scopus (20) Google Scholar PDAC cells responding to T/P exposed increased levels of MHC class I molecules on their surface, which favored CTL activation in a diverse experimental setting harnessing the model antigen ovalbumin. However, CTL depletion failed to affect the partial therapeutic activity of T/P in immunocompetent PDAC models, largely reflecting the exhausted phenotype of CTLs infiltrating T/P-treated PDACs, which encompassed high surface levels of the co-inhibitory receptor programmed cell death 1 (PDCD1, best known as PD-1). Consistent with this, co-administration of a PD-1 blocker favored the activation of PDAC-infiltrating CTLs, correlating with superior therapeutic activity in vivo. Globally corroborating the working model from Lowe and collaborators (Figure 1), the therapeutic effects of T/P plus a PD-1 blocker were compromised when p65 was downregulated in PDAC cells, KDR or VCAM1 were antagonized, or CTLs were depleted.1Ruscetti M. Morris J.P.t. Mezzadra R. Russell J. Leibold J. Romesser P.B. Simon J. Kulick A. Ho Y.J. Fennell M. et al.Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer.Cell. 2020; 181: 424-441Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Interestingly, pharmacological inhibition of KRASG12C has been reported to mediate immunostimulatory effects linked to immunogenic cell death (ICD)7Galluzzi L. Vitale I. Warren S. Adjemian S. Agostinis P. Martinez A.B. Chan T.A. Coukos G. Demaria S. Deutsch E. et al.Consensus guidelines for the definition, detection and interpretation of immunogenic cell death.J. Immunother. Cancer. 2020; 8: e000337Crossref PubMed Scopus (120) Google Scholar in a variety of KRASG12C-driven tumor models.8Canon J. Rex K. Saiki A.Y. Mohr C. Cooke K. Bagal D. Gaida K. Holt T. Knutson C.G. Koppada N. et al.The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.Nature. 2019; 575: 217-223Crossref PubMed Scopus (439) Google Scholar Consistent with this, the KRASG12C inhibitor AMG 510 synergized with a PD-1 blocker in the eradication of KRASG12C-expressing mouse colorectal tumors established in immunocompetent syngeneic mice,8Canon J. Rex K. Saiki A.Y. Mohr C. Cooke K. Bagal D. Gaida K. Holt T. Knutson C.G. Koppada N. et al.The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.Nature. 2019; 575: 217-223Crossref PubMed Scopus (439) Google Scholar hence resembling T/P in mice bearing KRAS-driven PDACs.1Ruscetti M. Morris J.P.t. Mezzadra R. Russell J. Leibold J. Romesser P.B. Simon J. Kulick A. Ho Y.J. Fennell M. et al.Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer.Cell. 2020; 181: 424-441Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Further supporting a role for ICD, PDACs exposed to T/P exhibited poor caspase 3 (CASP3) activation, and recruited high amounts of (exhausted) CTLs,1Ruscetti M. Morris J.P.t. Mezzadra R. Russell J. Leibold J. Romesser P.B. Simon J. Kulick A. Ho Y.J. Fennell M. et al.Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer.Cell. 2020; 181: 424-441Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar whereas (1) neoplastic lesions undergoing non-immunogenic cell death are characterized by robust CASP3 activation and poor infiltration by immune cells,7Galluzzi L. Vitale I. Warren S. Adjemian S. Agostinis P. Martinez A.B. Chan T.A. Coukos G. Demaria S. Deutsch E. et al.Consensus guidelines for the definition, detection and interpretation of immunogenic cell death.J. Immunother. Cancer. 2020; 8: e000337Crossref PubMed Scopus (120) Google Scholar and (2) cellular senescence per se preferentially recruit NK cells.5Ruscetti M. Leibold J. Bott M.J. Fennell M. Kulick A. Salgado N.R. Chen C.C. Ho Y.J. Sanchez-Rivera F.J. Feucht J. et al.NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination.Science. 2018; 362: 1416-1422Crossref PubMed Scopus (95) Google Scholar,9Kang T.W. Yevsa T. Woller N. Hoenicke L. Wuestefeld T. Dauch D. Hohmeyer A. Gereke M. Rudalska R. Potapova A. et al.Senescence surveillance of pre-malignant hepatocytes limits liver cancer development.Nature. 2011; 479: 547-551Crossref PubMed Scopus (785) Google Scholar,10Galluzzi L. Yamazaki T. Kroemer G. Linking cellular stress responses to systemic homeostasis.Nat. Rev. Mol. Cell Biol. 2018; 19: 731-745Crossref PubMed Scopus (134) Google Scholar However, whether PDAC cells exposed to T/P in vitro elicit prophylactic immunity (once inoculated in tumor-naive, immunocompetent, syngeneic mice) against living cells of the same type (which would be indicative of ICD induction) remains to be determined. Irrespective of these unknowns, the findings by Lowe and collaborators suggest that combining T/P and a PD-1 blocker (all of which are approved by the USFDA for cancer therapy) stands out as a promising approach for patients with PDAC. Clinical trials investigating the safety and efficacy of this combinatorial regimen are awaited. Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas CancerRuscetti et al.CellMarch 31, 2020In BriefIn mouse models of KRAS mutant pancreatic ductal adenocarcinoma, tumor cell senescence following MEK and CDK4/6 inhibition promotes vascular remodeling through induction of a pro-angiogenic senescence-associated secretory phenotype, leading to enhanced drug delivery and T cell infiltration that sensitizes these tumors to chemotherapy and immune checkpoint blockade. Full-Text PDF Open Archive