Wennerberg, E.
Mukherjee, S.
Spada, S.
Hung, C.
Agrusa, C.J.
Chen, C.
Valeta-Magara, A.
Rudqvist, N.-.
Van Nest, S.J.
Kamel, M.K.
Nasar, A.
Narula, N.
Mittal, V.
Markowitz, G.J.
Zhou, X.K.
Adusumilli, P.S.
Borczuk, A.C.
White, T.E.
Khan, A.G.
Balderes, P.J.
Lorenz, I.C.
Altorki, N.
Demaria, S.
McGraw, T.E.
Stiles, B.M.
(2022). Expression of the mono-ADP-ribosyltransferase ART1 by tumor cells mediates immune resistance in non-small cell lung cancer. ,
Vol.14
(636),
p. eabe8195.
show abstract
Most patients with non-small cell lung cancer (NSCLC) do not achieve durable clinical responses from immune checkpoint inhibitors, suggesting the existence of additional resistance mechanisms. Nicotinamide adenine dinucleotide (NAD)-induced cell death (NICD) of P2X7 receptor (P2X7R)-expressing T cells regulates immune homeostasis in inflamed tissues. This process is mediated by mono-adenosine 5'-diphosphate (ADP)-ribosyltransferases (ARTs). We found an association between membranous expression of ART1 on tumor cells and reduced CD8 T cell infiltration. Specifically, we observed a reduction in the P2X7R+ CD8 T cell subset in human lung adenocarcinomas. In vitro, P2X7R+ CD8 T cells were susceptible to ART1-mediated ADP-ribosylation and NICD, which was exacerbated upon blockade of the NAD+-degrading ADP-ribosyl cyclase CD38. Last, in murine NSCLC and melanoma models, we demonstrate that genetic and antibody-mediated ART1 inhibition slowed tumor growth in a CD8 T cell-dependent manner. This was associated with increased infiltration of activated P2X7R+CD8 T cells into tumors. In conclusion, we describe ART1-mediated NICD as a mechanism of immune resistance in NSCLC and provide preclinical evidence that antibody-mediated targeting of ART1 can improve tumor control, supporting pursuit of this approach in clinical studies..
Yamazaki, T.
Wennerberg, E.
Hensler, M.
Buqué, A.
Kraynak, J.
Fucikova, J.
Zhou, X.K.
Sveinbjørnsson, B.
Rekdal, Ø.
Demaria, S.
Galluzzi, L.
(2021). LTX-315-enabled, radiotherapy-boosted immunotherapeutic control of breast cancer by NK cells. Oncoimmunology,
Vol.10
(1).
Vitale, I.
Yamazaki, T.
Wennerberg, E.
Sveinbjørnsson, B.
Rekdal, Ø.
Demaria, S.
Galluzzi, L.
(2021). Targeting Cancer Heterogeneity with Immune Responses Driven by Oncolytic Peptides. Trends in cancer,
.
show abstract
Accumulating preclinical and clinical evidence indicates that high degrees of heterogeneity among malignant cells constitute a considerable obstacle to the success of cancer therapy. This calls for the development of approaches that operate - or enable established treatments to operate - despite such intratumoral heterogeneity (ITH). In this context, oncolytic peptides stand out as promising therapeutic tools based on their ability to drive immunogenic cell death associated with robust anticancer immune responses independently of ITH. We review the main molecular and immunological pathways engaged by oncolytic peptides, and discuss potential approaches to combine these agents with modern immunotherapeutics in support of superior tumor-targeting immunity and efficacy in patients with cancer..
Wennerberg, E.
Spada, S.
Rudqvist, N.-.
Lhuillier, C.
Gruber, S.
Chen, Q.
Zhang, F.
Zhou, X.K.
Gross, S.S.
Formenti, S.C.
Demaria, S.
(2020). CD73 Blockade Promotes Dendritic Cell Infiltration of Irradiated Tumors and Tumor Rejection. Cancer immunology research,
Vol.8
(4),
pp. 465-478.
show abstract
The ability of focal radiotherapy to promote priming of tumor-specific CD8+ T cells and increase responses to immunotherapy is dependent on infiltration of the tumor by Batf3-dependent conventional dendritic cell type 1 (cDC1) cells. Such infiltration is driven by radiotherapy-induced IFN type I (IFN-I). Other signals may also modulate cDC1 infiltration of irradiated tumors. Here we found increased expression of adenosine-generating enzymes CD38 and CD73 in irradiated mouse and human breast cancer cells and increased adenosine in mouse tumors following radiotherapy. CD73 blockade alone had no effect. CD73 blockade with radiotherapy restored radiotherapy-induced cDC1 infiltration of tumors in settings where radiotherapy induction of IFN-I was suboptimal. In the absence of radiotherapy-induced IFN-I, blockade of CD73 was required for rejection of the irradiated tumor and for systemic tumor control (abscopal effect) in the context of cytotoxic T-lymphocyte-associated protein 4 blockade. These results suggest that CD73 may be a radiation-induced checkpoint, and that CD73 blockade in combination with radiotherapy and immune checkpoint blockade might improve patient response to therapy..
Wennerberg, E.
Lhuillier, C.
Rybstein, M.D.
Dannenberg, K.
Rudqvist, N.-.
Koelwyn, G.J.
Jones, L.W.
Demaria, S.
(2020). Exercise reduces immune suppression and breast cancer progression in a preclinical model. Oncotarget,
Vol.11
(4),
pp. 452-461.
show abstract
Exercise is associated with favorable changes in circulating immune cells and improved survival in early-stage breast cancer patients, but the mechansims remain to be fully elucidated. Preclinical studies indicate that physical activity started before tumor injection reduces tumor incidence and progression. Here we tested whether exercise has anti-tumor effects in mice with established 4T1 mammary carcinoma, a mouse model of triple negative breast cancer. Exercise slowed tumor progression and reduced the tumor-induced accumulation of myeloid-derived suppressor cells (MDSCs). The reduction in MDSCs was accompanied by a relative increase in natural killer and CD8 T cell activation, suggesting that exercise restores a favorable immune environment. Consistently, exercise improved responses to a combination of programmed cell death protein 1 (PD-1) blockade and focal radiotherapy. These data support further investigations of exercise in breast cancer patients treated with combinations of immunotherapy and cytotoxic agents to improve cancer outcomes..
Spada, S.
Rudqvist, N.-.
Wennerberg, E.
(2020). Isolation of DNA from exosomes. ,
,
pp. 173-183.
Wennerberg, E.
Galluzzi, L.
(2019). Born to Kill: NK Cells Go to War against Cancer. Trends in cancer,
Vol.5
(3),
pp. 143-145.
Rudqvist, N.-.
Pilones, K.A.
Lhuillier, C.
Wennerberg, E.
Sidhom, J.-.
Emerson, R.O.
Robins, H.S.
Schneck, J.
Formenti, S.C.
Demaria, S.
(2018). Radiotherapy and CTLA-4 Blockade Shape the TCR Repertoire of Tumor-Infiltrating T Cells. Cancer immunology research,
Vol.6
(2),
pp. 139-150.
show abstract
AbstractImmune checkpoint inhibitors activate T cells to reject tumors. Unique tumor mutations are key T-cell targets, but a comprehensive understanding of the nature of a successful antitumor T-cell response is lacking. To investigate the T-cell receptor (TCR) repertoire associated with treatment success versus failure, we used a well-characterized mouse carcinoma that is rejected by CD8 T cells in mice treated with radiotherapy (RT) and anti–CTLA-4 in combination, but not as monotherapy, and comprehensively analyzed tumor-infiltrating lymphocytes (TILs) by high-throughput sequencing of the TCRΒ CDR3 region. The combined treatment increased TIL density and CD8/CD4 ratio. Assessment of the frequency of T-cell clones indicated that anti–CTLA-4 resulted in fewer clones and a more oligoclonal repertoire compared with untreated tumors. In contrast, RT increased the CD8/CD4 ratio and broadened the TCR repertoire, and when used in combination with anti–CTLA-4, these selected T-cell clones proliferated. Hierarchical clustering of CDR3 sequences showed a treatment-specific clustering of TCRs that were shared by different mice. Abundant clonotypes were commonly shared between animals and yet treatment-specific. Analysis of amino-acid sequence similarities revealed a significant increase in the number and richness of dominant CDR3 motifs in tumors treated with RT + anti–CTLA-4 compared with control. The repertoire of TCRs reactive with a single tumor antigen recognized by CD8+ T cells was heterogeneous but highly clonal, irrespective of treatment. Overall, data support a model whereby a diverse TCR repertoire is required to achieve tumor rejection and may underlie the synergy between RT and CTLA-4 blockade. Cancer Immunol Res; 6(2); 139–50. ©2017 AACR..
Formenti, S.C.
Rudqvist, N.-.
Golden, E.
Cooper, B.
Wennerberg, E.
Lhuillier, C.
Vanpouille-Box, C.
Friedman, K.
Ferrari de Andrade, L.
Wucherpfennig, K.W.
Heguy, A.
Imai, N.
Gnjatic, S.
Emerson, R.O.
Zhou, X.K.
Zhang, T.
Chachoua, A.
Demaria, S.
(2018). Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nature medicine,
Vol.24
(12),
pp. 1845-1851.
Wennerberg, E.
Vanpouille‐Box, C.
Bornstein, S.
Yamazaki, T.
Demaria, S.
Galluzzi, L.
(2017). Immune recognition of irradiated cancer cells. Immunological reviews,
Vol.280
(1),
pp. 220-230.
Kremer, V.
Ligtenberg, M.A.
Zendehdel, R.
Seitz, C.
Duivenvoorden, A.
Wennerberg, E.
Colón, E.
Scherman-Plogell, A.-.
Lundqvist, A.
(2017). Genetic engineering of human NK cells to express CXCR2 improves migration to renal cell carcinoma. Journal for immunotherapy of cancer,
Vol.5
(1).
Mao, Y.
van Hoef, V.
Zhang, X.
Wennerberg, E.
Lorent, J.
Witt, K.
Masvidal, L.
Liang, S.
Murray, S.
Larsson, O.
Kiessling, R.
Lundqvist, A.
(2016). IL-15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells. Blood,
Vol.128
(11),
pp. 1475-1489.
show abstract
Key Points
Cytokine-activated NK cells display distinct gene expression programs in response to cytokine withdrawal. IL-15 sustains antitumor functions of NK cells through mTOR-governed metabolic processes..
Wennerberg, E.
Kremer, V.
Childs, R.
Lundqvist, A.
(2015). CXCL10-induced migration of adoptively transferred human natural killer cells toward solid tumors causes regression of tumor growth in vivo. Cancer immunology, immunotherapy,
Vol.64
(2),
pp. 225-235.
Vanpouille-Box, C.
Pilones, K.A.
Wennerberg, E.
Formenti, S.C.
Demaria, S.
(2015). In situ vaccination by radiotherapy to improve responses to anti-CTLA-4 treatment. Vaccine,
Vol.33
(51),
pp. 7415-7422.
Koelwyn, G.J.
Wennerherg, E.
Demria, S.
Jones, L.W.
(2015). Exercise in Regulation of Inflammation-Immune Axis Function in Cancer Initiation and Progression. Oncology-new york,
Vol.29
(12),
pp. 908-+.
Tittarelli, A.
Mendoza-Naranjo, A.
Farías, M.
Guerrero, I.
Ihara, F.
Wennerberg, E.
Riquelme, S.
Gleisner, A.
Kalergis, A.
Lundqvist, A.
López, M.N.
Chambers, B.J.
Salazar-Onfray, F.
(2014). Gap Junction Intercellular Communications Regulate NK Cell Activation and Modulate NK Cytotoxic Capacity. The journal of immunology,
Vol.192
(3),
pp. 1313-1319.
Magnusson, S.E.
Wennerberg, E.
Matt, P.
Lindqvist, U.
Kleinau, S.
(2014). Dysregulated Fc receptor function in active rheumatoid arthritis. Immunology letters,
Vol.162
(1),
pp. 200-206.
Wennerberg, E.
Pfefferle, A.
Ekblad, L.
Yoshimoto, Y.
Kremer, V.
Kaminskyy, V.O.
Juhlin, C.C.
Höög, A.
Bodin, I.
Svjatoha, V.
Larsson, C.
Zedenius, J.
Wennerberg, J.
Lundqvist, A.
(2014). Human Anaplastic Thyroid Carcinoma Cells Are Sensitive to NK Cell–Mediated Lysis via ULBP2/5/6 and Chemoattract NK Cells. Clinical cancer research,
Vol.20
(22),
pp. 5733-5744.
show abstract
Abstract
Purpose: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive forms of cancer with no curative therapies available. To date, strategies to target ATC by immunotherapy have not been evaluated. We investigated whether ATC would be a suitable target for natural killer (NK) cell–based immunotherapy.
Experimental Design: We first established seven new cell lines from ATC tumors, three from papillary thyroid carcinoma tumors and analyzed them together with eight additional ATC cell lines. Cells were analyzed for sensitivity to lysis by NK cells and their ability to chemoattract and regulate the activity of NK cells. In addition, fresh tumor samples and peripheral blood from six patients with ATC were analyzed for NK cell infiltration and phenotype.
Results: We observed that ATC cell lines are sensitive to lysis by ex vivo expanded NK cells and that the lysis was abrogated upon blockade of NKG2D. Sensitivity of thyroid cancer cell lines to NK cell–mediated lysis correlated with surface expression of UL16-binding protein 2 on tumor cells. Moreover, ATC cell lines produced high levels of CXCL10 and stimulated migration of expanded NK cells and ATC tumors were enriched for NK cells expressing the cognate chemokine receptor CXCR3. However, compared with NK cells in peripheral blood, ATC tumor–derived NK cells displayed a suppressed phenotype with a downregulated expression of NKG2D. In vitro, suppression of NK cell–mediated lysis and NKG2D expression by ATC cells was restored upon neutralization of prostaglandin-E2.
Conclusions: ATC cell lines are sensitive to NK cell–mediated lysis via ULBP2/5/6 and chemoattract CXCR3-positive NK cells. Patients with ATC may benefit from NK cell–based immunotherapy. Clin Cancer Res; 20(22); 5733–44. ©2014 AACR..
Mao, Y.
Poschke, I.
Wennerberg, E.
Pico de Coaña, Y.
Egyhazi Brage, S.
Schultz, I.
Hansson, J.
Masucci, G.
Lundqvist, A.
Kiessling, R.
(2013). Melanoma-Educated CD14+ Cells Acquire a Myeloid-Derived Suppressor Cell Phenotype through COX-2–Dependent Mechanisms. Cancer research,
Vol.73
(13),
pp. 3877-3887.
show abstract
Abstract
Tumors can suppress the host immune system by employing a variety of cellular immune modulators, such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells (MDSC). In the peripheral blood of patients with advanced stage melanoma, there is an accumulation of CD14+HLA-DRlo/− MDSC that suppress autologous T cells ex vivo in a STAT-3–dependent manner. However, a precise mechanistic basis underlying this effect is unclear, particularly with regard to whether the MDSC induction mechanism relies on cell–cell contact of melanoma cells with CD14+ cells. Here, we show that early-passage human melanoma cells induce phenotypic changes in CD14+ monocytes, leading them to resemble MDSCs characterized in patients with advanced stage melanoma. These MDSC-like cells potently suppress autologous T-cell proliferation and IFN-γ production. Notably, induction of myeloid-suppressive functions requires contact or close proximity between monocytes and tumor cells. Further, this induction is largely dependent on production of cyclooxygenase-2 (COX-2) because its inhibition in these MDSC-like cells limits their ability to suppress T-cell function. We confirmed our findings with CD14+ cells isolated from patients with advanced stage melanoma, which inhibited autologous T cells in a manner relying up prostaglandin E2 (PGE2), STAT-3, and superoxide. Indeed, PGE2 was sufficient to confer to monocytes the ability to suppress proliferation and IFN-γ production by autologous T cells ex vivo. In summary, our results reveal how immune suppression by MDSC can be initiated in the tumor microenvironment of human melanoma. Cancer Res; 73(13); 3877–87. ©2013 AACR..
Wennerberg, E.
Sarhan, D.
Carlsten, M.
Kaminskyy, V.O.
D'Arcy, P.
Zhivotovsky, B.
Childs, R.
Lundqvist, A.
(2013). Doxorubicin sensitizes human tumor cells to NK cell- and T-cell-mediated killing by augmented TRAIL receptor signaling. International journal of cancer,
Vol.133
(7),
pp. 1643-1652.
Sarhan, D.
D'Arcy, P.
Wennerberg, E.
Lidén, M.
Hu, J.
Winqvist, O.
Rolny, C.
Lundqvist, A.
(2013). Activated monocytes augment TRAIL-mediated cytotoxicity by human NK cells through release of IFN-γ. European journal of immunology,
Vol.43
(1),
pp. 249-257.
Sarhan, D.
Wennerberg, E.
D’Arcy, P.
Gurajada, D.
Linder, S.
Lundqvist, A.
(2013). A novel inhibitor of proteasome deubiquitinating activity renders tumor cells sensitive to TRAIL-mediated apoptosis by natural killer cells and T cells. Cancer immunology, immunotherapy,
Vol.62
(8),
pp. 1359-1368.
Okita, R.
Mougiakakos, D.
Ando, T.
Mao, Y.
Sarhan, D.
Wennerberg, E.
Seliger, B.
Lundqvist, A.
Mimura, K.
Kiessling, R.
(2012). HER2/HER3 Signaling Regulates NK Cell-Mediated Cytotoxicity via MHC Class I Chain-Related Molecule A and B Expression in Human Breast Cancer Cell Lines. The journal of immunology,
Vol.188
(5),
pp. 2136-2145.
Kiessling, R.
Okita, R.
Mougiakakos, D.
Mao, Y.
Sarhan, D.
Wennerberg, E.
Seliger, B.
Lundqvist, A.
Mimura, K.
Kono, K.
(2012). Opposing consequences of signaling through EGF family members. Oncoimmunology,
Vol.1
(7),
pp. 1200-1201.
Wennerberg, E.
Lhuillier, C.
Vanpouille-Box, C.
Pilones, K.A.
García-Martínez, E.
Rudqvist, N.-.
Formenti, S.C.
Demaria, S.
Barriers to Radiation-Induced In Situ Tumor Vaccination. Frontiers in immunology,
Vol.8.
Karasarides, M.
Cogdill, A.P.
Robbins, P.B.
Bowden, M.
Burton, E.M.
Butterfield, L.H.
Cesano, A.
Hammer, C.
Haymaker, C.L.
Horak, C.E.
McGee, H.M.
Monette, A.
Rudqvist, N.-.
Spencer, C.N.
Sweis, R.F.
Vincent, B.G.
Wennerberg, E.
Yuan, J.
Zappasodi, R.
Lucey, V.M.
Wells, D.K.
LaVallee, T.
Hallmarks of Resistance to Immune-Checkpoint Inhibitors. Cancer immunology research,
Vol.10
(4),
pp. 372-383.
show abstract
Immune-checkpoint inhibitors (ICI), although revolutionary in improving long-term survival outcomes, are mostly effective in patients with immune-responsive tumors. Most patients with cancer either do not respond to ICIs at all or experience disease progression after an initial period of response. Treatment resistance to ICIs remains a major challenge and defines the biggest unmet medical need in oncology worldwide. In a collaborative workshop, thought leaders from academic, biopharma, and nonprofit sectors convened to outline a resistance framework to support and guide future immune-resistance research. Here, we explore the initial part of our effort by collating seminal discoveries through the lens of known biological processes. We highlight eight biological processes and refer to them as immune resistance nodes. We examine the seminal discoveries that define each immune resistance node and pose critical questions, which, if answered, would greatly expand our notion of immune resistance. Ultimately, the expansion and application of this work calls for the integration of multiomic high-dimensional analyses from patient-level data to produce a map of resistance phenotypes that can be utilized to guide effective drug development and improved patient outcomes..