JITC Editor Picks
Lorena Carmona-Rodríguez, Diego Martínez-Rey, Maria Jesús Fernández-Aceñero, Alicia González-Martín, Mateo Paz-Cabezas, Noe Rodríguez-Rodríguez, Beatriz Pérez-Villamil, Maria Eugenia Sáez, Eduardo Díaz-Rubio, Emilia Mira, Santos Mañes
Journal for ImmunoTherapy of Cancer 2020;8:e000432 (25 June 2020)
Research
Summary:
Tumors exclude infiltrating lymphocytes by cell-intrinsic and extrinsic mechanisms, including aberrant activation of the WNT/beta-catenin pathway and vascular dysfunction. Lorena Carmona Rodríguez et al identify a new mechanism that regulates immune cell infiltration into tumors, centered around SOD3. Overexpression of SOD3 in endothelial cells increased CD3+ T cell adhesion and transmigration in vitro for both naïve and ex vivo activated cells. In mice bearing LLC tumors, overexpression of SOD3 in the tumor microenvironment via either the administration of an adenoviral vector or lovastatin led to delayed tumor growth and extended survival, but only when the animals were first treated with doxorubicin to induce immunogenic cell death. In adoptive transfer experiments, the numbers of tumor-infiltrating lymphocytes correlated with tumor control. Overexpression of SOD3 did not lead to any significant changes in chemokine levels in the supernatants of cultured cells or in tumors in vivo. Downstream of SOD3, endothelial overexpression of HIF-2 alpha enhanced transmigration of CD4+ and CD8+ T cells in vitro. Compartment-specific knockout of HIF-2 alpha in endothelial cells led to reduced tumor T cell infiltration and eliminated the effects of SOD3 overexpression on tumor control. Both in vitro and in vivo, HIF-2 alpha silencing reduced expression of WISP2 mRNA, which encodes a non-conventional WNT ligand. Expression of the WNT-regulated basement membrane component LAMA4 was also induced by SOD3 in vitro and in vivo. Analysis of a tissue microarray of 95 primary stage II colorectal carcinomas showed that SOD3 positivity was associated with enhanced endothelial WNT signaling, increased LAM4 staining in neoplastic and stromal cells and CD8+ T cell density. The results highlight the basement membrane as a potential new target to promote immune cell infiltration to enhance anti-tumor responses.
Simon P Keam, Heloise Halse, Thu Nguyen, Minyu Wang, Nicolas Van Kooten Losio, Catherine Mitchell, Franco Caramia, David J Byrne, Sue Haupt, Georgina Ryland, Phillip K Darcy, Shahneen Sandhu, Piers Blombery, Ygal Haupt, Scott G Williams, Paul J Neeson.
Journal for ImmunoTherapy of Cancer 2020;8:e000792 (24 June 2020)
Research
Summary:
Localized prostate cancer has a profoundly immunosuppressed phenotype with tumor-associated lymphocytes present only at the margins and excluded from within the tumor. To determine whether the standard curative intent treatment, high dose-rate brachytherapy (HDRBT) alters prostate immune context, Simon P Keam et al performed NanoString immune gene expression profiling, digital spatial profiling, and high-throughput immune cell multiplex immunohistochemistry analysis on pre- and post-radiation tissue samples from a cohort of 24 patients. Using the NanoString nCounter PanCancer Immune Profiling platform, 59 highly significant genes were differentially expressed after HDRBT, a response that was diverse and included innate, humoral, adaptive, and inflammatory immunity. Digital spatial profiling revealed that the HDRBT-induced inflammatory signature was broadly driven by a mix of infiltrative immune cells includes CD8+ T cells, Tregs, macrophages, and dendritic cells. Additionally, several immune checkpoint molecules were significantly upregulated after HDRBT. Although the overall density of immune cell subsets in the prostate as a whole was not affected by radiation, in tumor zones, both Tregs and CD4+ T cells were more associated with PD-L1+ HMWCK- cells after HDBRT while the interaction of PD-L1- dendritic cells with their PD-L1+ counterparts and with PD-L1+ macrophages and B cells was preferentially lost. In multivariate analysis, the main spatial response to radiation that drove inflammatory gene expression response was a decrease in distance between T cells and dendritic cells and macrophages and dendritic cells in both tumor and nontumor zones. The findings suggest that HDBRT could perturb the tumor microenvironment in such a way that immunotherapy may improve outcomes in prostate cancer patients.
Matteo Libero Baroni, Diego Sanchez Martinez, Francisco Gutierrez Aguera, Heleia Roca Ho, Maria Castella, Samanta Romina Zanetti, Talia Velasco Hernandez, Rafael Diaz de la Guardia, Julio Castaño, Eduardo Anguita, Susana Vives, Josep Nomdedeu, Helene Lapillone, Anne E Bras, Vincent H J van der Velden, Jordi Junca, Pedro Marin, Alex Bataller, Jordi Esteve, Binje Vick, Irmela Jeremias, Angel Lopez, Marc Sorigue, Clara Bueno, Pablo Menendez
Journal for ImmunoTherapy of Cancer 2020;8:e000845 (10 June 2020)
Research
Summary:
The development of chimeric antigen receptor (CAR) T cell immunotherapies for acute myeloid leukemia (AML) has been hindered by both highly heterogeneous expression of target antigens on malignant cells and shared expression of target antigens with normal hematopoietic stem/progenitor cells (HSPCs). To identify a viable target for AML immunotherapy, Matteo Libero Baroni and colleagues analyzed 97 primary samples both from the time of diagnosis and at relapse and found that CD123 was the most common and homogeneously expressed antigen. Patient-derived CD3+ T cells could be successfully transfected with lentiviral vectors carrying second generation anti-CD123 CARs, and the resulting manufactured CAR T cells generated high levels of proinflammatory cytokines IL-2, TNF-alpha and IFN-gamma when cocultured with AML cell lines regardless if they were based on a CD28 or a 41BB costimulatory domain. Importantly, though, both CD28- and 41BB-based anti-CD123 CAR T cells were profoundly myeloablative in vitro. In xenograft models, anti-CD123 CAR T cells controlled disease while also hampering the viability and clonogenic capacity of CD34+ HSPCs. In xenograft models of human engraftment in the presence of existing hematopoiesis, CD28-based CD123 CARTs proved less myeloablative than 41BB-CD123 CARTs. Both costimulatory domains, however, prevented healthy hematopoietic reconstitution in models of de novo engraftment of HSPCs. The findings emphasize a need for caution when clinically implementing CD123 CAR T cell therapies.
Victoria A Brentville, Rachael L Metheringham, Ian Daniels, Suha Atabani, Peter Symonds, Katherine W Cook, Mireille Vankemmelbeke, Ruhul Choudhury, Poonam Vaghela, Mohamed Gijon, Ghislaine Meiners, Willem-Jan Krebber, Cornelis J M Melief, Lindy G Durrant
Journal for ImmunoTherapy of Cancer 2020;8:e000560 (18 June 2020)
Research
Summary:
Under conditions of cellular stress such as occurs within tumors, citrullination within the autophagosome can lead to new epitopes that elicit robust T cell responses when presented by MHC class II. To develop novel antigens, Victoria A Brentville and colleagues created a vaccine based on a combination of three citrullinated peptides: two derived from vimentin and one derived from enolase. In HLA-transgenic mice, vaccination with the mixture elicited high-frequency peptide specific responses with no evidence of immunodominance for one antigen over any other. Vaccination of melanoma and ovarian tumor-bearing mice led to regression, and responses were more pronounced when the peptide mixture was combined with a TLR9/TLR4 adjuvant. Additionally, vaccination protected against rechallenge. Tumor regression after vaccination correlated with increases in infiltrating CD4+ T cells and decreases in myeloid-derived suppressor cells. Depletion of CD4+ T cells eliminated the antitumor effects of the vaccine. A variety of adjuvants, including TLR9/TLR4, TLR3, GM-CSF and TLR2 agonists, elicited high frequencies of citrullinated peptide-specific T cells after vaccination. Linking a TLR1/2 agonist allowed for the vaccine to confer a significant survival advantage in an aggressive model of melanoma in mice, even at 100-fold lower doses than previously used. In PBMCs from ovarian cancer patients, the vaccine peptides elicited CD4+ T cell proliferative responses and interferon gamma and granzyme B expression. The study makes a case for further translation of the citrullinated peptide vaccine into the clinic.
Adi Reches, Yael Ophir, Natan Stein, Inbal Kol, Batya Isaacson, Yoav Charpak Amikam, Afek Elnekave, Pinchas Tsukerman, Paola Kucan Brlic, Tihana Lenac, Barbara Seliger, Stipan Jonjic, Ofer Mandelboim
Journal for ImmunoTherapy of Cancer 2020;8:e000266 (5 June 2020)
Research
Summary:
Several investigational checkpoint inhibitors targeting the T-cell immunoreceptor with Ig and ITIM domains (TIGIT) have entered clinical trials. Adi Reches and colleagues identify a potentially promising new target for checkpoint inhibition in Nectin4, a novel TIGIT ligand with strictly restricted expression that is limited to tumor cells. Nectin4 showed similar in vitro binding affinity to TIGIT as PVR as measured by microscale thermophoresis, and the ligand-receptor interaction led to reduced cytotoxicity in primary human natural killer (NK) cells. In mice implanted with Nectin4 overexpressing Raji cells (a transfectable human lymphoblastoid cell line derived from a patient with Burkitt’s lymphoma) and human NK cells, administration of anti-Nectin4 monoclonal antibodies slowed tumor growth. The anti-Nectin4 antibodies also slowed tumor growth when mice were implanted with human NK cells and MDA-MB-453 tumors (which are derived from breast cancer and express Nectin4 along with additional ligands in the Nectin family). Analysis of gene expression data from lung adenocarcinoma patients and colon cancer patients revealed that high Nectin4 expression was associated with worse overall survival. Targeting Nectin4 may prove to be an effective strategy for cancer immunotherapy with less likelihood of immune-related adverse events.
David S Hong, Aparna Parikh, Geoffrey I Shapiro, Andrea Varga, Aung Naing, Funda Meric-Bernstam, Özlem Ataman, Larisa Reyderman, Terri A Binder, Min Ren, Mingjie Liu, Satish Dayal, Amy Y Siu, Pallavi Sachdev, Lucy Xu, Vijay Bhagawati-Prasad, Ilian Tchakov, Chean Eng Ooi, Xingfeng Bao, Aurelien Marabelle
Journal for ImmunoTherapy of Cancer 2020;8:e000222 (17 June 2020)
Research
Summary:
Tumors exploit the effects of prostaglandins on monocytic cell differentiation and T cell activation in order to maintain an immunosuppressive microenvironment. Based on pre-clinical evidence that E7046, a highly selective, small-molecule antagonist of the E-type prostanoid receptor 4 (EP4), inhibited the growth of multiple mouse syngeneic tumor models, David S Hong and colleagues enrolled 30 patients with advanced tumors of cancer types associated with high levels of myeloid infiltrates in a first-in-human clinical trial. E7046 was administered orally once-daily in sequential escalating dose cohorts with 6 or more patients per cohort. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. Treatment-related adverse events (AEs) occurred in 16 patients (53%) and grade 3 or higher treatment-related AEs occurred in three patients (10%). No objective responses were observed by irRECIST—stable disease was observed in seven patients (23%), and the disease control rate was 23%. Stable disease was observed across several dose levels examined, and exposure to study drug increased dose proportionally up to 500 mg. Paired tumor biopsies before treatment and on cycle 2 day 1 revealed significant increases in CD3+ and CD8+ T cells as well as changes in the levels of key EP4-regulated genes, including upregulation of tumor necrosis factor alpha and C-X-C motif chemokine ligand 10 (CXCL10), although the increases did not reach statistical significance. Serum levels of the T cell recruiting cytokines CXCL10 and C-C motif chemokine ligand 5 (CCL5) were significantly upregulated on treatment. The study shows that E7046 treatment was associated with manageable toxicity. Two doses, 250 mg and 500 mg, were chosen as the recommended phase II dose for future clinical investigation.