Cooperation between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors

Dangaj, Denarda; Bruand, Marine; Grimm, Alizée J.; Ronet, Catherine; Barras, David; Duttagupta, Priyanka; Lanitis, Evripidis; Duraiswamy, Jaikumar; Tanyi, János L.; Benencia, Fabián; Conejo-Garcia, José R.; Ramay, Hena R.; Montone, Kathleen T.; Powell, Daniel J.; Gimotty, Phyllis A.; Facciabene, Andrea; Jackson, Donald; Weber, Jeffrey S.; Rodig, Scott J.; Hodi, Stephen; Kandalaft, Lana E.; Irving, Melita; Zhang, Lin; Foukas, Periklis; Rusakiewicz, Sylvie; Delorenzi, Mauro; Coukos, George

doi:10.1016/j.ccell.2019.05.004

Cited by 556 publications

(534 citation statements)

References 67 publications

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“…Tumor expression of chemokines including CCL5 (Dangaj et al, 2019), CXCL10 (Peng et al, 2015) and the cytokine CSF2 (Borrello et al, 2009) have been linked with the ability of T cells to infiltrate and control tumor growth, and we found that increased mRNA expression of these genes is positively correlated with NFKB2 expression in human melanoma patients (Figure S5A-C). Consistent with a role for non-canonical NF-kB in promoting inflammatory chemokine production, we found increased abundance of RelB at the CXCL10 promoter in BIRC2 KO tumor cells ( Figure 7A).…”

Section: Birc2 Loss Promotes Increased T Cell Migration and Recognitimentioning

confidence: 85%

“…Consistent with previous reports in the setting of B cell malignancies (Yang et al, 2016), we found that BIRC2 acts as an important negative regulator of the non-canonical NF-kB signaling cascade. Activation of non-canonical NF-kB signaling by genetic deletion of BIRC2 promoted increased tumor cell destruction by upregulating tumor cell antigen presentation pathways and the production of pro-inflammatory chemokines that have been linked with clinical responses to immunotherapy (Dangaj et al, 2019;Harlin et al, 2009;Peng et al, 2015). It is notable that the expression of non-canonical NF-kB transcription factor NFKB2 was positively correlated with survival in patients treated with CTLA blockade (Van Allen et al, 2015) and that NFKB2 and IRF1 expression could predict responses across several clinical cohorts of human immunotherapy patients.…”

Section: Discussionmentioning

confidence: 99%

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Genome-wide profiling of druggable active tumor defense mechanisms to enhance cancer immunotherapy

Kishton

Patel

Vodnala

et al. 2019

Preprint

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All current highly effective anti-tumor immunotherapeutics depend on the activity of T cells, but tumor cells can escape immune recognition by several mechanisms including loss of function in antigen presentation and inflammatory response genes, expression of immunomodulatory proteins and an immunosuppressive tumor microenvironment. In contrast, the comprehensive identification of strategies that sensitize tumor cells to immunotherapy in vivo has remained challenging. Here, we combine a two-cell type (2CT) whole-genome CRISPR-Cas9 screen with dynamic transcriptional analysis (DTA) of tumor upon T cell encounter to identify a set of genes that tumor cells express as an active defense against T cell-mediated killing. We then employed small molecule and biologic screens designed to antagonize gene products employed by tumor cells to actively defend against T cell-mediated tumor destruction and found that the inhibition of BIRC2, ITGAV or DNPEP enhanced tumor cell destruction by T cells. Mechanistically, we found that BIRC2 promoted immunotherapy resistance through inhibiting non-canonical NF-kB signaling and limiting inflammatory chemokine production.These findings show the path forward to improving T cell-mediated tumor destruction in the clinic.3

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Section: Birc2 Loss Promotes Increased T Cell Migration and Recognitimentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Genome-wide profiling of druggable active tumor defense mechanisms to enhance cancer immunotherapy

Kishton

Patel

Vodnala

et al. 2019

Preprint

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“…CCL5 and CXCL9 also correlated in this analysis, and dual expression of these chemokines was associated with better prognosis. Interestingly, ovarian cancers with high intra-tumor CD8+ cells but low CCL5 had high levels of CXCL9 transcripts (Dangaj et al, 2019). By contrast, high levels of tumor-associated macrophages, particularly M2-like macrophages, and MDSCs correlate with poor outcome (Drakes and Stiff, 2018;Ruffell and Coussens, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, high levels of tumor-associated macrophages, particularly M2-like macrophages, and MDSCs correlate with poor outcome (Drakes and Stiff, 2018;Ruffell and Coussens, 2015). Aside from describing greater T cell infiltration and better prognosis in BRCA-mutant tumors (Clarke et al, 2009;Rodriguez et al, 2018;Strickland et al, 2016) and examining the regulatory mechanism of specific immune regulatory molecules (e.g., silencing of CCL5 transcription) (Dangaj et al, 2019), these studies are tumor genotype-agnostic. Yet the three mouse models that we examine in detail display major differences in TME, as well as significant differences in chemokine and cytokine gene expression, including tumors where CXCL10 likely directs T cell influx, and others in which T cell influx is associated with Cxcl9.…”

Section: Discussionmentioning

confidence: 99%

Genetically Defined, Syngeneic Organoid Platform for Developing Combination Therapies for Ovarian Cancer

Neel

zhang

Iyer

et al. 2020

Preprint

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SUMMARYThe paucity of genetically informed, immune-competent tumor models impedes evaluation of conventional, targeted, and immune therapies. By engineering mouse fallopian tube (FT) organoids using lentiviral gene transduction and/or CRISPR/Cas9 mutagenesis, we generated multiple high grade serous ovarian carcinoma (HGSOC) models exhibiting mutational combinations seen in patients. Detailed analysis of homologous recombination (HR)-proficient (Tp53-/-;Ccne1OE;Akt2OE; KrasOE), HR-deficient (Tp53-/-;Brca1-/-;MycOE) and unclassified (Tp53-/-;Pten-/-;Nf1-/-) organoids revealed differences in in vitro properties and tumorigenicity. Tumorigenic organoids had variable sensitivity to HGSOC chemotherapeutics and evoked distinct immune microenvironments. These findings enabled development of a chemotherapy/immunotherapy regimen that yielded durable, T-cell dependent responses in Tp53-/-;Ccne1OE;Akt2OE;Kras HGSOC; by contrast, Tp53-/-;Pten-/-;Nf1-/- tumors failed to respond. Genotype-informed, syngeneic organoid models could provide an improved platform for rapid evaluation of tumor biology and therapeutics.HIGHLIGHTSOrthotopic injection of genetically defined fallopian tube organoids yield HGSOC.Ovarian tumors with different genotypes evoke distinct immune microenvironmentsCombining Gemcitabine, anti-PD-L1, and anti-CTLA-4 result in complete responses in Tp53-/-;Ccne1OE;Akt2OE;KrasOE organoid-derived HGSOCTherapeutic response is tumor genotype-specific

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“…Reports from our group and others have shown that the chemotactic cytokine CCL5 is widely overexpressed in malignant lesions, directs infiltration of T cells and indicates better prognosis of patients with different types of tumors. [12][13][14][15] As the most important receptor for CCL5, CCR5 is indispensable for the site-specific localization of immune cells. NK cells are also recruited by CCL5 via CCR5.…”

Section: Introductionmentioning

confidence: 99%

CCL5-armed oncolytic virus augments CCR5-engineered NK cell infiltration and antitumor efficiency

Sheng

Hou

et al. 2020

J Immunother Cancer

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BackgroundNatural killer (NK) cells have potent antitumor activities. Nevertheless, adoptive transfer therapy of NK cells has gained very limited success in patients with solid tumors as most infused NK cells remain circulating in the peripheral blood instead of entering tumor sites. Chemokines and their receptors play important roles in NK cell distribution. Enhancing chemokine receptors on immune cells to match and be driven to tumor-specific chemokines may improve the therapeutic efficacy of NK cells.MethodsThe CCR5-CCL5 axis is critical in NK cell homing to tumor sites. Thus, we analyzed CCR5 expression on NK cells from patients with cancer and healthy donors. We then upregulated CCR5 and CCL5 with lentiviruses and oncolytic viruses in NK and tumor cells, respectively. Animal experiments were also carried out to test the efficacy of the combination of oncolytic virus with NK cells.ResultsIn NK cells from patients with various solid tumors or healthy subjects, CCR5 was expressed at low levels before and after expansion in vitro. CCR5-engineered NK cells showed enhanced tumor infiltration and antitumor effects, but no complete regressions were noted in the in vivo tumor models. To further improve therapeutic efficacy, we constructed CCL5-expressing oncolytic vaccinia virus. In vitro data demonstrated that vaccinia virus can produce CCL5 in tumor cells while infectivity remained unaffected. Supernatants from tumor cells infected by CCL5-modified vaccinia virus enhanced the directional movement of CCR5-overexpressed NK cells but not green fluorescent protein (GFP)-expressing cells. More importantly, NK cells were resistant to the vaccinia virus and their functions were not affected after being in contact. In vivo assays demonstrated that CCL5-expressing vaccinia virus induced a greater accumulation of NK cells within tumor lesions compared with that of the prototype virus.ConclusionEnhancement of matched chemokines and chemokine receptors is a promising method of increasing NK cell homing and therapeutic effects. Oncolytic vaccinia viruses that express specific chemokines can synergistically augment the efficacies of NK cell-based therapy.

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Cooperation between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors

Cited by 556 publications

References 67 publications

Genome-wide profiling of druggable active tumor defense mechanisms to enhance cancer immunotherapy

Genome-wide profiling of druggable active tumor defense mechanisms to enhance cancer immunotherapy

Genetically Defined, Syngeneic Organoid Platform for Developing Combination Therapies for Ovarian Cancer

CCL5-armed oncolytic virus augments CCR5-engineered NK cell infiltration and antitumor efficiency

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