bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Data from Adoptive Cellular Therapy with Autologous Tumor-Infiltrating Lymphocytes and T-cell Receptor–Engineered T Cells Targeting Common p53 Neoantigens in Human Solid Tumors
Authors: Kim Sanghyun P. , Vale Nolan R. , Zacharakis Nikolaos , Krishna Sri , Yu Zhiya , Gasmi Billel , Gartner Jared J. , Sindiri Sivasish , Malekzadeh Parisa , Deniger Drew C. , Lowery Frank J. , Parkhurst Maria R. , Ngo Lien T. , Ray Satyajit , Li Yong F. , Hill Victoria , Florentin Maria , Masi Robert V. , Paria Biman C. , Levin Noam , Bera Alakesh , Hedges Elizabeth A. , Choi Agnes , Chatani Praveen D. , Parikh Anup Y. , Levi Shoshana , Seitter Samantha , Lu Yong-Chen , Zheng Zhili , Prickett Todd D. , Jia Li , Hernandez Jonathan M. , Hoang Chuong D. , Robbins Paul F. , Goff Stephanie L. , Sherry Richard M. , Yang James C. , Rosenberg Steven A.
Published: April 2023

Supplementary Data from Adoptive Cellular Therapy with Autologous Tumor-Infiltrating Lymphocytes and T-cell Receptor–Engineered T Cells Targeting Common p53 Neoantigens in Human Solid Tumors
Supplementary Figure from Tyrosine Kinase Inhibition Alters Intratumoral CD8+ T-cell Subtype Composition and Activity
Authors: Tieniber Andrew D. , Hanna Andrew N. , Medina Benjamin D. , Vitiello Gerardo A. , Etherington Mark S. , Liu Mengyuan , Do Kevin J. , Rossi Ferdinando , DeMatteo Ronald P.
Published: April 2023

Supplementary Figure from Tyrosine Kinase Inhibition Alters Intratumoral CD8+ T-cell Subtype Composition and Activity
Supplementary Figure from Preclinical Characterization and Phase I Study of an Anti–HER2-TLR7 Immune-Stimulator Antibody Conjugate in Patients with HER2+ Malignancies
Authors: Janku Filip , Han Sae-Won , Doi Toshihiko , Amatu Alessio , Ajani Jaffer A. , Kuboki Yasutoshi , Cortez Alex , Cellitti Susan E. , Mahling Ping C. , Subramanian Kulandayan , Schoenfeld Heidi A. , Choi Sarah M. , Iaconis Lori A. , Lee Lang Ho , Pelletier Marc R. , Dranoff Glenn , Askoxylakis Vasileios , Siena Salvatore
Published: April 2023

Supplementary Figure from Preclinical Characterization and Phase I Study of an Anti–HER2-TLR7 Immune-Stimulator Antibody Conjugate in Patients with HER2+ Malignancies
Supplementary Tables from Protection of Regulatory T Cells from Fragility and Inactivation in the Tumor Microenvironment
Authors: Zhang Hongru , Tomar Vivek S. , Li Jinyang , Basavaraja Raghavendra , Yan Fangxue , Gui Jun , McBrearty Noreen , Costich Tara Lee , Beiting Daniel P. , Blanco M. Andres , Conejo-Garcia Jose R. , Saggu Gurpanna , Berger Allison , Nefedova Yulia , Gabrilovich Dmitry I. , Fuchs Serge Y.
Published: April 2023

Supplementary Tables 1, 2, and 3
Supplementary Figure from Protection of Regulatory T Cells from Fragility and Inactivation in the Tumor Microenvironment
Authors: Zhang Hongru , Tomar Vivek S. , Li Jinyang , Basavaraja Raghavendra , Yan Fangxue , Gui Jun , McBrearty Noreen , Costich Tara Lee , Beiting Daniel P. , Blanco M. Andres , Conejo-Garcia Jose R. , Saggu Gurpanna , Berger Allison , Nefedova Yulia , Gabrilovich Dmitry I. , Fuchs Serge Y.
Published: April 2023

Supplementary Figure from Protection of Regulatory T Cells from Fragility and Inactivation in the Tumor Microenvironment
Supplementary Data from Suppression of Tumor or Host Intrinsic CMTM6 Drives Antitumor Cytotoxicity in a PD-L1–Independent Manner
Authors: Long Yiru , Chen Runqiu , Yu Xiaolu , Tong Yongliang , Peng Xionghua , Li Fanglin , Hu Chao , Sun Jianhua , Gong Likun
Published: April 2023

Supplementary Table and Figures S1-S21
Supplementary Table 1 from CD161 Characterizes an Inflamed Subset of Cytotoxic T Lymphocytes Associated with Prolonged Survival in Human Papillomavirus–Driven Oropharyngeal Cancer
Authors: Wei Ye , Xu Tingting , Li Chong , Zhou Xin , Qian Wei , Shen Chunying , Wang Qifeng , Xing Xing , Ou Xiaomin , He Xiayun , Yin Hongmei , Hu Chaosu , Wang Yu , Ji Qinghai , Su Fengtao , Lu Xueguan
Published: April 2023

Supplementary Table 1
Supplementary Figures from CD161 Characterizes an Inflamed Subset of Cytotoxic T Lymphocytes Associated with Prolonged Survival in Human Papillomavirus–Driven Oropharyngeal Cancer
Authors: Wei Ye , Xu Tingting , Li Chong , Zhou Xin , Qian Wei , Shen Chunying , Wang Qifeng , Xing Xing , Ou Xiaomin , He Xiayun , Yin Hongmei , Hu Chaosu , Wang Yu , Ji Qinghai , Su Fengtao , Lu Xueguan
Published: April 2023

Supplementary figures and legends
Supplementary Figures from Characterization of Leukemic Resistance to CD19-Targeted CAR T-cell Therapy through Deep Genomic Sequencing
Authors: Chen Gregory M. , Chen Chia-Hui , Perazzelli Jessica , Grupp Stephan A. , Barrett David M. , Tan Kai
Published: April 2023

Supplementary Figure 1-9.
Table S1 from Cancer Cell Resistance to IFNγ Can Occur via Enhanced Double-Strand Break Repair Pathway Activity
Authors: Han Tong , Wang Xujun , Shi Sailing , Zhang Wubing , Wang Jue , Wu Qiu , Li Ziyi , Fu Jingxin , Zheng Rongbin , Zhang Jiamin , Tang Qin , Zhang Peng , Wang Chenfei
Published: April 2023

IFN-γ sensitivity of cancer cells (n = 43) from CCLE (sheet1); Gene sets enrichment for highly expressed gene sets in IFN-γ resistant/sensitive cell lines using CCLE transcriptomic dataset (sheet2-3).
Supplementary Figure 7 and 8 from Antigen-Loaded Extracellular Vesicles Induce Responsiveness to Anti–PD-1 and Anti–PD-L1 Treatment in a Checkpoint Refractory Melanoma Model
Authors: Veerman Rosanne E. , Akpinar Gözde Güclüler , Offens Annemarijn , Steiner Loïc , Larssen Pia , Lundqvist Andreas , Karlsson Mikael C.I. , Gabrielsson Susanne
Published: April 2023

Figure S7: MHCI and PD-L1 on IFNy-stimulated B16 cells, and tumor growth of these cells. Figure S8: Tumor growth and survival mice after late treatment with anti-PD-1/PD-L1 in combination with EVs
Supplementary Figure 6 from Antigen-Loaded Extracellular Vesicles Induce Responsiveness to Anti–PD-1 and Anti–PD-L1 Treatment in a Checkpoint Refractory Melanoma Model
Authors: Veerman Rosanne E. , Akpinar Gözde Güclüler , Offens Annemarijn , Steiner Loïc , Larssen Pia , Lundqvist Andreas , Karlsson Mikael C.I. , Gabrielsson Susanne
Published: April 2023

Mean growth curve of tumors in prophylactic setting and percentage of T cells in splenocytes of mice with vs without tumor development
Supplementary Figure 5 from Antigen-Loaded Extracellular Vesicles Induce Responsiveness to Anti–PD-1 and Anti–PD-L1 Treatment in a Checkpoint Refractory Melanoma Model
Authors: Veerman Rosanne E. , Akpinar Gözde Güclüler , Offens Annemarijn , Steiner Loïc , Larssen Pia , Lundqvist Andreas , Karlsson Mikael C.I. , Gabrielsson Susanne
Published: April 2023

Upregulation of functional markers on DCs after in vitro exposure to EVs.
Supplementary Figure 2 from Antigen-Loaded Extracellular Vesicles Induce Responsiveness to Anti–PD-1 and Anti–PD-L1 Treatment in a Checkpoint Refractory Melanoma Model
Authors: Veerman Rosanne E. , Akpinar Gözde Güclüler , Offens Annemarijn , Steiner Loïc , Larssen Pia , Lundqvist Andreas , Karlsson Mikael C.I. , Gabrielsson Susanne
Published: April 2023

Gating strategy for OVA-specific CD8 T cells in splenocytes
Figure S4 from VISTA Targeting of T-cell Quiescence and Myeloid Suppression Overcomes Adaptive Resistance
Authors: Schaafsma Evelien , Croteau Walburga , ElTanbouly Mohamed , Nowak Elizabeth C. , Smits Nicole C. , Deng Jie , Sarde Aurelien , Webber Cecilia A. , Rabadi Dina , Cheng Chao , Noelle Randolph , Lines J. Louise
Published: April 2023

Supplementary Figure S4. Additional data supporting Figure 6. In the I/V model, BALB/c mice were administered 100k CT26 cells and treated when tumors reached a size of 40mm3 with isotype (I) or anti-VISTA (V). In the CPV model, BALB/c mice were administered 100k CT26 cells and treated with anti-CTLA-4 and anti-PD-1 plus isotype (CP) or plus anti-VISTA (CPV) when tumors reached a size of 600mm3. CD45 + (A-C, E) or CD8+ AH1-tetramer+ (D) cells were isolated from the TME and analyzed by scRNAseq. (A) Stacked bar graph showing all lymphoid cluster frequencies as a proportion of the lymphoid infiltrate for I/V and CP/CPV. (B) Stacked bar graph showing NK cluster frequencies as a proportion of the NK infiltrate for I/V and CP/CPV. (C) Stacked bar graph showing CD8+ T cell cluster frequencies as a proportion of the CD8+ T cell infiltrate for I/V and CP/CPV. (D) Mean cluster frequencies as a proportion of CD8+ AH1-tetramer+ T cells in I/V or CP/CPV treatment. (E) Violin plots showing enrichment of a quiescence gene signature in CD8+ T cell clusters in the CD45 + sorted I/V dataset[58]. *P < 0.05, **P < 0.01, ***P < 0.001.
Figure S2 from VISTA Targeting of T-cell Quiescence and Myeloid Suppression Overcomes Adaptive Resistance
Authors: Schaafsma Evelien , Croteau Walburga , ElTanbouly Mohamed , Nowak Elizabeth C. , Smits Nicole C. , Deng Jie , Sarde Aurelien , Webber Cecilia A. , Rabadi Dina , Cheng Chao , Noelle Randolph , Lines J. Louise
Published: April 2023

Additional data supporting Figure 3. (A) Pathway enrichment for each cluster described in figure 3. (B) Comparison of myeloid clusters from this study with those identified by [30]. Dots represent the proportion of myeloid clusters described in this study (bottom) in the Gubin et al. myeloid clusters (left). Each row is normalized by row sums. Cluster identity from [30] was obtained from the original publication. (C) Cluster frequencies as a proportion of the myeloid infiltrate in I/V or CP/CPV treatment.
Figures S1-S6 from PHD2 Constrains Antitumor CD8+ T-cell Activity
Authors: Bisilliat Donnet Charlotte , Acolty Valérie , Azouz Abdulkader , Taquin Anaëlle , Henin Coralie , Trusso Cafarello Sarah , Denanglaire Sébastien , Mazzone Massimiliano , Oldenhove Guillaume , Leo Oberdan , Goriely Stanislas , Moser Muriel
Published: April 2023

Supplementary figures
Supplementary file 5 from Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer
Authors: Lidström Tommy , Cumming Joshua , Gaur Rahul , Frängsmyr Lars , Pateras Ioannis S. , Mickert Matthias J. , Franklin Oskar , Forsell Mattias N.E. , Arnberg Niklas , Dongre Mitesh , Patthey Cedric , Öhlund Daniel
Published: April 2023

Raw read count, normalized expression values (TPM) and sample metadata for bulk RNA sequencing data
Supplementary file 4 from Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer
Authors: Lidström Tommy , Cumming Joshua , Gaur Rahul , Frängsmyr Lars , Pateras Ioannis S. , Mickert Matthias J. , Franklin Oskar , Forsell Mattias N.E. , Arnberg Niklas , Dongre Mitesh , Patthey Cedric , Öhlund Daniel
Published: April 2023

Lists of genes used to calculate signature scores for cytolytic activity, T cell activation and M1 vs M2 macrophage polarization in single cell data analysis
Supplementary file 3 from Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer
Authors: Lidström Tommy , Cumming Joshua , Gaur Rahul , Frängsmyr Lars , Pateras Ioannis S. , Mickert Matthias J. , Franklin Oskar , Forsell Mattias N.E. , Arnberg Niklas , Dongre Mitesh , Patthey Cedric , Öhlund Daniel
Published: April 2023

Top 30 markers of clusters in CAF subset of single cell data
Supplementary file 2 from Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer
Authors: Lidström Tommy , Cumming Joshua , Gaur Rahul , Frängsmyr Lars , Pateras Ioannis S. , Mickert Matthias J. , Franklin Oskar , Forsell Mattias N.E. , Arnberg Niklas , Dongre Mitesh , Patthey Cedric , Öhlund Daniel
Published: April 2023

Top 30 markers of clusters in Immune subset of single cell data
Supplementary file 1 from Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer
Authors: Lidström Tommy , Cumming Joshua , Gaur Rahul , Frängsmyr Lars , Pateras Ioannis S. , Mickert Matthias J. , Franklin Oskar , Forsell Mattias N.E. , Arnberg Niklas , Dongre Mitesh , Patthey Cedric , Öhlund Daniel
Published: April 2023

Metadata and single cell annotation for all 7677 cells in single cell dataset
Supplementary Tables from Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer
Authors: Lidström Tommy , Cumming Joshua , Gaur Rahul , Frängsmyr Lars , Pateras Ioannis S. , Mickert Matthias J. , Franklin Oskar , Forsell Mattias N.E. , Arnberg Niklas , Dongre Mitesh , Patthey Cedric , Öhlund Daniel
Published: April 2023

Supplementary Tables
Supplementary Figures from High-Resolution Analysis of Mononuclear Phagocytes Reveals GPNMB as a Prognostic Marker in Human Colorectal Liver Metastasis
Authors: Cortese Nina , Carriero Roberta , Barbagallo Marialuisa , Putignano Anna Rita , Costa Guido , Giavazzi Fabio , Grizzi Fabio , Pasqualini Fabio , Peano Clelia , Basso Gianluca , Marchini Sergio , Colombo Federico Simone , Soldani Cristiana , Franceschini Barbara , Di Tommaso Luca , Terracciano Luigi , Donadon Matteo , Torzilli Guido , Kunderfranco Paolo , Mantovani Alberto , Marchesi Federica
Published: April 2023

Supplementary Figures 1-4, Tables S1 and S5
Supplementary Fig. S1 - S12 from Tissue-Resident Memory T Cells in Pancreatic Ductal Adenocarcinoma Coexpress PD-1 and TIGIT and Functional Inhibition Is Reversible by Dual Antibody Blockade
Authors: Pearce Hayden , Croft Wayne , Nicol Samantha M. , Margielewska-Davies Sandra , Powell Richard , Cornall Richard , Davis Simon J. , Marcon Francesca , Pugh Matthew R. , Fennell Éanna , Powell-Brett Sarah , Mahon Brinder S. , Brown Rachel M. , Middleton Gary , Roberts Keith , Moss Paul
Published: April 2023

Supplementary Figures S1 - S12
Supplementary Data from Tumor Cell–Derived Microparticles Induced by Methotrexate Augment T-cell Antitumor Responses by Downregulating Expression of PD-1 in Neutrophils
Authors: Xu Pingwei , Zhang Xiaojie , Chen Kai , Zhu Meng , Jia Ru , Zhou Qingwei , Yang Jintao , Dai Juqin , Jin Yuepeng , Shi Keqing
Published: April 2023

supplementary figures 1-7 and table S1
Supplementary Table 1 from Autoantibodies Drive Heart Damage Caused by Concomitant Radiation and PD-1 Blockade
Authors: Yan Bo , Hooper D. Craig , Yuan Zhiyong , Wang Changli , Chen Yulong , Lu Bo
Published: April 2023

Supplementary Table 1
Supplementary Figure 3 from Autoantibodies Drive Heart Damage Caused by Concomitant Radiation and PD-1 Blockade
Authors: Yan Bo , Hooper D. Craig , Yuan Zhiyong , Wang Changli , Chen Yulong , Lu Bo
Published: April 2023

Supplementary Figure 3
Data from Treg Depletion Licenses T Cell–Driven HEV Neogenesis and Promotes Tumor Destruction
Authors: Colbeck Emily J. , Jones Emma , Hindley James P. , Smart Kathryn , Schulz Ralph , Browne Molly , Cutting Scott , Williams Anwen , Parry Lee , Godkin Andrew , Ware Carl F. , Ager Ann , Gallimore Awen
Published: April 2023

Abstract
T-cell infiltration into tumors represents a critical bottleneck for immune-mediated control of cancer. We previously showed that this bottleneck can be overcome by depleting immunosuppressive Foxp3+ regulatory T cells (Tregs), a process that can increase frequencies of tumor-infiltrating lymphocytes through promoting the development of specialized portals for lymphocyte entry, namely high endothelial venules (HEVs). In this paper, we used a carcinogen-induced tumor model that allows for coevolution of the tumor microenvironment and the immune response to demonstrate that Treg depletion not only results in widespread disruption to HEV networks in lymph nodes (LNs) but also activates CD8+ T cells, which then drive intratumoral HEV development. Formation of these vessels contrasts with ontogenic HEV development in LNs in that the process is dependent on the TNF receptor and independent of lymphotoxin β receptor–mediated signaling. These intratumoral HEVs do not express the chemokine CCL21, revealing a previously undescribed intratumoral blood vessel phenotype. We propose a model where Treg depletion enables a self-amplifying loop of T-cell activation, which promotes HEV development, T-cell infiltration, and ultimately, tumor destruction. The findings point to a need to test for HEV development as part of ongoing clinical studies in patients with cancer. Cancer Immunol Res; 5(11); 1005–15. ©2017 AACR.
Data from CD16A Activation of NK Cells Promotes NK Cell Proliferation and Memory-Like Cytotoxicity against Cancer Cells
Authors: Pahl Jens H.W. , Koch Joachim , Götz Jana-Julia , Arnold Annette , Reusch Uwe , Gantke Thorsten , Rajkovic Erich , Treder Martin , Cerwenka Adelheid
Published: April 2023

Abstract
CD16A is a potent cytotoxicity receptor on human natural killer (NK) cells, which can be exploited by therapeutic bispecific antibodies. So far, the effects of CD16A-mediated activation on NK cell effector functions beyond classical antibody-dependent cytotoxicity have remained poorly elucidated. Here, we investigated NK cell responses after exposure to therapeutic antibodies such as the tetravalent bispecific antibody AFM13 (CD30/CD16A), designed for the treatment of Hodgkin lymphoma and other CD30+ lymphomas. Our results reveal that CD16A engagement enhanced subsequent IL2- and IL15-driven NK cell proliferation and expansion. This effect involved the upregulation of CD25 (IL2Rα) and CD132 (γc) on NK cells, resulting in increased sensitivity to low-dose IL2 or to IL15. CD16A engagement initially induced NK cell cytotoxicity. The lower NK cell reactivity observed 1 day after CD16A engagement could be recovered by reculture in IL2 or IL15. After reculture in IL2 or IL15, these CD16A-experienced NK cells exerted more vigorous IFNγ production upon restimulation with tumor cells or cytokines. Importantly, after reculture, CD16A-experienced NK cells also exerted increased cytotoxicity toward different tumor targets, mainly through the activating NK cell receptor NKG2D. Our findings uncover a role for CD16A engagement in priming NK cell responses to restimulation by cytokines and tumor cells, indicative of a memory-like functionality. Our study suggests that combination of AFM13 with IL2 or IL15 may boost NK cell antitumor activity in patients by expanding tumor-reactive NK cells and enhancing NK cell reactivity, even upon repeated tumor encounters. Cancer Immunol Res; 6(5); 517–27. ©2018 AACR.
Data from BET Bromodomain Inhibition Cooperates with PD-1 Blockade to Facilitate Antitumor Response in Kras-Mutant Non–Small Cell Lung Cancer
Authors: Adeegbe Dennis O. , Liu Shengwu , Hattersley Maureen M. , Bowden Michaela , Zhou Chensheng W. , Li Shuai , Vlahos Raven , Grondine Michael , Dolgalev Igor , Ivanova Elena V. , Quinn Max M. , Gao Peng , Hammerman Peter S. , Bradner James E. , Diehl J. Alan , Rustgi Anil K. , Bass Adam J. , Tsirigos Aristotelis , Freeman Gordon J. , Chen Huawei , Wong Kwok-Kin
Published: April 2023

Abstract
KRAS mutation is present in approximately 30% of human lung adenocarcinomas. Although recent advances in targeted therapy have shown great promise, effective targeting of KRAS remains elusive, and concurrent alterations in tumor suppressors render KRAS-mutant tumors even more resistant to existing therapies. Contributing to the refractoriness of KRAS-mutant tumors are immunosuppressive mechanisms, such as increased presence of suppressive regulatory T cells (Treg) in tumors and elevated expression of the inhibitory receptor PD-1 on tumor-infiltrating T cells. Treatment with BET bromodomain inhibitors is beneficial for hematologic malignancies, and they have Treg-disruptive effects in a non–small cell lung cancer (NSCLC) model. Targeting PD-1–inhibitory signals through PD-1 antibody blockade also has substantial therapeutic impact in lung cancer, although these outcomes are limited to a minority of patients. We hypothesized that the BET bromodomain inhibitor JQ1 would synergize with PD-1 blockade to promote a robust antitumor response in lung cancer. In the present study, using Kras+/LSL-G12D; Trp53L/L (KP) mouse models of NSCLC, we identified cooperative effects between JQ1 and PD-1 antibody. The numbers of tumor-infiltrating Tregs were reduced and activation of tumor-infiltrating T cells, which had a T-helper type 1 (Th1) cytokine profile, was enhanced, underlying their improved effector function. Furthermore, lung tumor–bearing mice treated with this combination showed robust and long-lasting antitumor responses compared with either agent alone, culminating in substantial improvement in the overall survival of treated mice. Thus, combining BET bromodomain inhibition with immune checkpoint blockade offers a promising therapeutic approach for solid malignancies such as lung adenocarcinoma. Cancer Immunol Res; 6(10); 1234–45. ©2018 AACR.
Data from Sustained Persistence of IL2 Signaling Enhances the Antitumor Effect of Peptide Vaccines through T-cell Expansion and Preventing PD-1 Inhibition
Authors: Sultan Hussein , Kumai Takumi , Fesenkova Valentyna I. , Fan Aaron E. , Wu Juan , Cho Hyun-Il , Kobayashi Hiroya , Harabuchi Yasuaki , Celis Esteban
Published: April 2023

Abstract
Peptide vaccines can be a successful and cost-effective way of generating T-cell responses against defined tumor antigens, especially when combined with immune adjuvants such as poly-IC. However, strong immune adjuvants can induce a collateral increase in numbers of irrelevant, nonspecific T cells, which limits the effectiveness of the peptide vaccines. Here, we report that providing prolonged IL2 signaling in the form of either IL2/anti-IL2 complexes or pegylated IL2 overcomes the competitive suppressive effect of irrelevant T cells, allowing the preferential expansion of antigen-specific T cells. In addition to increasing the number of tumor-reactive T cells, sustained IL2 enhanced the ability of T cells to resist PD-1–induced negative signals, increasing the therapeutic effectiveness of the vaccines against established tumors. This vaccination strategy using peptides and sustained IL2 could be taken into the clinic for the treatment of cancer. Cancer Immunol Res; 6(5); 617–27. ©2018 AACR.
Data from PI3Kγ Activates Integrin α4 and Promotes Immune Suppressive Myeloid Cell Polarization during Tumor Progression
Authors: Foubert Philippe , Kaneda Megan M. , Varner Judith A.
Published: April 2023

Abstract
Immunosuppressive myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) accumulate in tumors where they inhibit T cell–mediated antitumor immune responses and promote tumor progression. Myeloid cell PI3Kγ plays a role in regulating tumor immune suppression by promoting integrin α4–dependent MDSC recruitment to tumors and by stimulating the immunosuppressive polarization of MDSCs and TAMs. Here, we show that integrin α4 promotes immunosuppressive polarization of MDSCs and TAMs downstream of PI3Kγ, thereby inhibiting antitumor immunity. Genetic or pharmacological suppression of either PI3Kγ or integrin α4 blocked MDSC recruitment to tumors and also inhibited immune suppressive myeloid cell polarization, thereby reducing expression of IL10 and increasing expression of IL12 and IFNγ within tumors. Inhibition of PI3Kγ or integrin α4 within tumors stimulated dendritic cell and CD8+ T-cell recruitment and maturation, as well as tumor cell cytotoxicity in vivo, thereby inhibiting tumor growth. As blockade of PI3Kγ or integrin α4 prevents accumulation of MDSC and reduces myeloid cell expression of immunosuppressive factors that stimulate tumor immune escape, these results highlight PI3Kγ and integrin α4 as targets for the design of cancer therapeutics. Cancer Immunol Res; 5(11); 957–68. ©2017 AACR.
Data from Escalating Regulation of 5T4-Specific IFN-γ+ CD4+ T Cells Distinguishes Colorectal Cancer Patients from Healthy Controls and Provides a Target for In Vivo Therapy
Authors: Scurr Martin , Bloom Anja , Pembroke Tom , Srinivasan Rohit , Brown Clare , Smart Kathryn , Bridgeman Hayley , Davies Mike , Hargest Rachel , Phillips Simon , Christian Adam , Hockey Tom , Gallimore Awen , Godkin Andrew
Published: April 2023

Abstract
The relationship between the adaptive CD4+ T-cell response and human cancer is unclear. The oncofetal antigen 5T4 is expressed in many human carcinomas, including colorectal cancer cells, but has limited expression on normal tissues. We previously identified anti-5T4 CD4+ T cells in a proportion of patients with colorectal cancer, and we extended this study to examine whether the quality or quantity of the T-cell response reflects tumor stage. An overlapping peptide library spanning 5T4 was used as a target to enumerate cognate IFN-γ+ CD4+ T cells [measured as spot-forming cells (SFC)/105 cultured T cells] in peripheral blood–derived lymphocytes following a 14-day in vitro culture period comparing patients preoperatively (n = 27) to healthy controls (n = 17). Robust 5T4-specific T-cell responses were present in 100% of healthy donors. There was a steady loss of T-cell responses with advancing tumors with a significant negative correlation from stage I to III (P = 0.008). The predictability of the decline meant <200 SFC/105 were only found in subjects with stage III colorectal cancer. The mechanism of loss of T-cell response is independent of HLA-DR type or patient age but does correspond to increases in Foxp3+ regulatory T cells (Treg). Using low-dose cyclophosphamide to reduce the proportion of Tregs in vivo resulted in increased anti-5T4 T-cell responses in patients with colorectal cancer. The selective loss of 5T4-specific IFN-γ+ CD4+ T-cell responses implies a link between tumor stage and antitumor Th1 effector function; depleting Tregs can enhance such responses. Cancer Immunol Res; 1(6); 416–25. ©2013 AACR.
Data from Autoantibody Development under Treatment with Immune-Checkpoint Inhibitors
Authors: de Moel Emma C. , Rozeman Elisa A. , Kapiteijn Ellen H. , Verdegaal Els M.E. , Grummels Annette , Bakker Jaap A. , Huizinga Tom W.J. , Haanen John B. , Toes René E.M. , van der Woude Diane
Published: April 2023

Abstract
Immune-checkpoint inhibitors (ICIs) activate the immune system to assault cancer cells in a manner that is not antigen specific. We hypothesized that tolerance may also be broken to autoantigens, resulting in autoantibody formation, which could be associated with immune-related adverse events (irAEs) and antitumor efficacy. Twenty-three common clinical autoantibodies in pre- and posttreatment sera from 133 ipilimumab-treated melanoma patients were determined, and their development linked to the occurrence of irAEs, best overall response, and survival. Autoantibodies developed in 19.2% (19/99) of patients who were autoantibody-negative pretreatment. A nonsignificant association was observed between development of any autoantibodies and any irAEs [OR, 2.92; 95% confidence interval (CI) 0.85–10.01]. Patients with antithyroid antibodies after ipilimumab had significantly more thyroid dysfunction under subsequent anti–PD-1 therapy: 7/11 (54.6%) patients with antithyroid antibodies after ipilimumab developed thyroid dysfunction under anti–PD1 versus 7/49 (14.3%) patients without antibodies (OR, 9.96; 95% CI, 1.94–51.1). Patients who developed autoantibodies showed a trend for better survival (HR for all-cause death: 0.66; 95% CI, 0.34–1.26) and therapy response (OR, 2.64; 95% CI, 0.85–8.16). We conclude that autoantibodies develop under ipilimumab treatment and could be a potential marker of ICI toxicity and efficacy.
Data from A Transient Increase in Eosinophils Is Associated with Prolonged Survival in Men with Metastatic Castration-Resistant Prostate Cancer Who Receive Sipuleucel-T
Authors: McNeel Douglas G. , Gardner Thomas A. , Higano Celestia S. , Kantoff Philip W. , Small Eric J. , Wener Mark H. , Sims Robert B. , DeVries Todd , Sheikh Nadeem A. , Dreicer Robert
Published: April 2023

Abstract
Sipuleucel-T is an autologous cellular immunotherapy used to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Traditional short-term indicators of clinical response commonly used with chemotherapy have not correlated with survival in patients treated with sipuleucel-T. This retrospective study aimed to evaluate laboratory parameters as possible early biomarkers associated with clinical benefit following sipuleucel-T treatment. Patients treated with sipuleucel-T from three randomized, controlled, phase III clinical trials in mCRPC were considered: IMPACT (NCT00065442; n = 512), D9901 (NCT00005947; n = 127), and D9902A (NCT01133704; n = 98). Patients from these trials were included in this study if their samples were analyzed by the central laboratory and if data were available from baseline and ≥1 posttreatment time point (n = 377). We found that sipuleucel-T treatment was associated with a transient increase in serum eosinophil count at week 6 that resolved by week 14 in 28% of patients (105 of 377). This eosinophil increase correlated with induced immune response, longer prostate cancer–specific survival [HR, 0.713; 95% confidence interval (CI), 0.525–0.970; P = 0.031], and a trend in overall survival (HR, 0.753; 95% CI, 0.563–1.008; P = 0.057). Median serum globulin protein levels also increased transiently, which was associated with antigen-specific antibody responses; however, this finding did not correlate with longer survival. We conclude that transient increases in eosinophils at week 6 may be a useful, objective, short-term indicator of global immune activation and survival benefit with sipuleucel-T in patients with mCRPC. This observation warrants prospective evaluation in future clinical trials. Cancer Immunol Res; 2(10); 988–99. ©2014 AACR.
Data from T-cell Localization, Activation, and Clonal Expansion in Human Pancreatic Ductal Adenocarcinoma
Authors: Stromnes Ingunn M. , Hulbert Ayaka , Pierce Robert H. , Greenberg Philip D. , Hingorani Sunil R.
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy resistant to most therapies, including immune checkpoint blockade. To elucidate mechanisms of immunotherapy resistance, we assessed immune parameters in resected human PDA. We demonstrate significant interpatient variability in T-cell number, localization, and phenotype. CD8+ T cells, Foxp3+ regulatory T cells, and PD-1+ and PD-L1+ cells were preferentially enriched in tertiary lymphoid structures that were found in most tumors compared with stroma and tumor cell nests. Tumors containing more CD8+ T cells also had increased granulocytes, CD163+ (M2 immunosuppressive phenotype) macrophages, and FOXP3+ regulatory T cells. PD-L1 was rare on tumor cells, but was expressed by CD163+ macrophages and an additional stromal cell subset commonly found clustered together adjacent to tumor epithelium. The majority of tumoral CD8+ T cells did not express molecules suggestive of recent T-cell receptor (TCR) signaling. However, 41BB+PD-1+ T cells were still significantly enriched in tumors compared with circulation. Tumoral CD8+PD-1+ T cells commonly expressed additional inhibitory receptors, yet were mostly T-BEThi and EOMESlo, consistent with a less terminally exhausted state. Analysis of gene expression and rearranged TCR genes by deep sequencing suggested most patients have a limited tumor-reactive T-cell response. Multiplex immunohistochemistry revealed variable T-cell infiltration based on abundance and location, which may result in different mechanisms of immunotherapy resistance. Overall, the data support the need for therapies that either induce endogenous, or provide engineered, tumor-specific T-cell responses, and concurrently relieve suppressive mechanisms operative at the tumor site. Cancer Immunol Res; 5(11); 978–91. ©2017 AACR.
Data from Programmed Cell Death Ligand 1 (PD-L1) Signaling Regulates Macrophage Proliferation and Activation
Authors: Hartley Genevieve P. , Chow Lyndah , Ammons Dylan T. , Wheat William H. , Dow Steven W.
Published: April 2023

Abstract
Tumor-associated macrophages (TAMs) express programmed cell death ligand 1 (PD-L1) and contribute to the immune-suppressive tumor microenvironment. Although the role of the PD-L1 and PD-1 interaction to regulate T-cell suppression is established, less is known about PD-L1 signaling in macrophages and how these signals may affect the function of TAMs. We used in vitro and in vivo models to investigate PD-L1 signaling in macrophages and the effects of PD-L1 antibody treatment on TAM responses. Treatment of mouse and human macrophages with PD-L1 antibodies increased spontaneous macrophage proliferation, survival, and activation (costimulatory molecule expression, cytokine production). Similar changes were observed in macrophages incubated with soluble CD80 and soluble PD-1, and in PD-L1−/− macrophages. Macrophage treatment with PD-L1 antibodies upregulated mTOR pathway activity, and RNAseq analysis revealed upregulation of multiple macrophage inflammatory pathways. In vivo, treatment with PD-L1 antibody resulted in increased tumor infiltration with activated macrophages. In tumor-bearing RAG−/− mice, upregulated costimulatory molecule expression by TAMs and reduced tumor growth were observed. Combined PD-1/ PD-L1 antibody treatment of animals with established B16 melanomas cured half of the treated mice, whereas treatment with single antibodies had little therapeutic effect. These findings indicate that PD-L1 delivers a constitutive negative signal to macrophages, resulting in an immune-suppressive cell phenotype. Treatment with PD-L1 antibodies reverses this phenotype and triggers macrophage-mediated antitumor activity, suggesting a distinct effect of PD-L1, but not PD-1, antibody treatment. Cancer Immunol Res; 6(10); 1260–73. ©2018 AACR.
Data from Assessment of MAGE-A Expression in Resected Non–Small Cell Lung Cancer in Relation to Clinicopathologic Features and Mutational Status of EGFR and KRAS
Authors: Ayyoub Maha , Memeo Lorenzo , Álvarez-Fernández Emilio , Colarossi Cristina , Costanzo Rosario , Aiello Eleonora , Martinetti Daniela , Valmori Danila
Published: April 2023

Abstract
Non–small cell lung cancer (NSCLC) is a major public health problem, accounting for more cancer-related deaths than any other cancer. Both immunotherapy, based on the expression of tumor-specific antigens, and targeted therapy, based on the presence of oncogenic mutations, are under development for NSCLC. In this study, we analyzed the expression of MAGE-A, a cancer–testis antigen, in tumors from a cohort of patients with resected NSCLC with respect to their clinicopathologic characteristics and their mutational status for the EGFR and KRAS genes. We found MAGE-A expression by IHC in 43% of the tumors. MAGE-A expression was significantly more frequent in squamous tumors than in adenocarcinomas, did not correlate with disease stage, but was correlated significantly with high tumor grade and worse survival. EGFR and KRAS mutations were present in adenocarcinomas, but not in squamous tumors. Whereas the presence of EGFR mutations did not seem to affect survival, the presence of KRAS mutations was associated with early-stage disease and better survival. MAGE-A expression was absent from adenocarcinomas with KRAS mutations, but not significantly different in tumors with or without EGFR mutations. Together, the reported results provide guidance for the design of combination therapies in patients with NSCLC. Cancer Immunol Res; 2(10); 943–8. ©2014 AACR.
Data from Polyamine-Blocking Therapy Reverses Immunosuppression in the Tumor Microenvironment
Authors: Hayes Candace S. , Shicora Allyson C. , Keough Martin P. , Snook Adam E. , Burns Mark R. , Gilmour Susan K.
Published: April 2023

Abstract
Correcting T-cell immunosuppression may unleash powerful antitumor responses; however, knowledge about the mechanisms and modifiers that may be targeted to improve therapy remains incomplete. Here, we report that polyamine elevation in cancer, a common metabolic aberration in aggressive lesions, contributes significantly to tumor immunosuppression and that a polyamine depletion strategy can exert antitumor effects that may also promote immunity. A polyamine-blocking therapy (PBT) that combines the well-characterized ornithine decarboxylase (ODC) inhibitor difluoromethylornithine (DFMO) with AMXT 1501, a novel inhibitor of the polyamine transport system, blocked tumor growth in immunocompetent mice but not in athymic nude mice lacking T cells. PBT had little effect on the proliferation of epithelial tumor cells, but it increased the number of apoptotic cells. Analysis of CD45+ tumor immune infiltrates revealed that PBT decreased levels of Gr-1+CD11b+ myeloid suppressor cells and increased CD3+ T cells. Strikingly, in a model of neoadjuvant therapy, mice administered with PBT one week before surgical resection of engrafted mammary tumors exhibited resistance to subsequent tumor rechallenge. Collectively, our results indicate that therapies targeting polyamine metabolism do not act exclusively as antiproliferative agents, but also act strongly to prevent immune escape by the tumor. PBT may offer a general approach to heighten immune responses in cancer. Cancer Immunol Res; 2(3); 274–85. ©2013 AACR.
Data from Combined Targeting of Costimulatory (OX40) and Coinhibitory (CTLA-4) Pathways Elicits Potent Effector T Cells Capable of Driving Robust Antitumor Immunity
Authors: Redmond William L. , Linch Stefanie N. , Kasiewicz Melissa J.
Published: April 2023

Abstract
Ligation of the TNF receptor family costimulatory molecule OX40 (CD134) with an agonist anti-OX40 monoclonal antibody (mAb) enhances antitumor immunity by augmenting T-cell differentiation as well as turning off the suppressive activity of the FoxP3+CD4+ regulatory T cells (Treg). In addition, antibody-mediated blockade of the checkpoint inhibitor CTLA-4 releases the “brakes” on T cells to augment tumor immunotherapy. However, monotherapy with these agents has limited therapeutic benefit particularly against poorly immunogenic murine tumors. Therefore, we examined whether the administration of agonist anti-OX40 therapy in the presence of CTLA-4 blockade would enhance tumor immunotherapy. Combined anti-OX40/anti-CTLA-4 immunotherapy significantly enhanced tumor regression and the survival of tumor-bearing hosts in a CD4 and CD8 T cell–dependent manner. Mechanistic studies revealed that the combination immunotherapy directed the expansion of effector T-bethigh/Eomeshigh granzyme B+ CD8 T cells. Dual immunotherapy also induced distinct populations of Th1 [interleukin (IL)-2, IFN-γ], and, surprisingly, Th2 (IL-4, IL-5, and IL-13) CD4 T cells exhibiting increased T-bet and Gata-3 expression. Furthermore, IL-4 blockade inhibited the Th2 response, while maintaining the Th1 CD4 and effector CD8 T cells that enhanced tumor-free survival. These data demonstrate that refining the global T-cell response during combination immunotherapy can further enhance the therapeutic efficacy of these agents. Cancer Immunol Res; 2(2); 142–53. ©2013 AACR.
Data from Apoptosis-Regulated Low-Avidity Cancer-Specific CD8+ T Cells Can Be Rescued to Eliminate HER2/neu–Expressing Tumors by Costimulatory Agonists in Tolerized Mice
Authors: Black Chelsea M. , Armstrong Todd D. , Jaffee Elizabeth M.
Published: April 2023

Abstract
A major barrier to vaccines in cancer treatment is their failure to activate and maintain a complete cancer-specific CD8+ effector T-cell repertoire. Low-avidity T cells are more likely to escape clonal deletion in the thymus when compared with high-avidity T cells, and therefore comprise the major population of effector T cells available for activation in patients with cancer. However, low-avidity T cells fail to traffic into the tumor microenvironment and function in eradicating tumor under optimal vaccination conditions as opposed to high-avidity T cells that escape clonal deletion and function in tumor killing. We used high- and low-avidity T-cell receptor transgenic CD8+ T cells specific for the immunodominant epitope HER2/neu (RNEU420–429) to identify signaling pathways responsible for the inferior activity of the low-avidity T cells. Adoptive transfer of these cells into tumor-bearing vaccinated mice identified the members of apoptosis pathways that are upregulated in low-avidity T cells. The increased expression of proapoptotic proteins by low-avidity T cells promoted their own cell death and also that of other tumor-specific CD8+ T cells within their local environment. Importantly, we show that this proapoptotic effect can be overcome by using a strong costimulatory signal that prevents the activation-induced cell death and enables the low-avidity T cells to traffic into the tumor and assist in tumor clearance. These findings identify new therapeutic opportunities for activating the most potent anticancer T-cell responses. Cancer Immunol Res; 2(4); 307–19. ©2014 AACR.
Data from Targeting Fibroblast Activation Protein in Tumor Stroma with Chimeric Antigen Receptor T Cells Can Inhibit Tumor Growth and Augment Host Immunity without Severe Toxicity
Authors: Wang Liang-Chuan S. , Lo Albert , Scholler John , Sun Jing , Majumdar Rajrupa S. , Kapoor Veena , Antzis Michael , Cotner Cody E. , Johnson Laura A. , Durham Amy C. , Solomides Charalambos C. , June Carl H. , Puré Ellen , Albelda Steven M.
Published: April 2023

Abstract
The majority of chimeric antigen receptor (CAR) T-cell research has focused on attacking cancer cells. Here, we show that targeting the tumor-promoting, nontransformed stromal cells using CAR T cells may offer several advantages. We developed a retroviral CAR construct specific for the mouse fibroblast activation protein (FAP), comprising a single-chain Fv FAP [monoclonal antibody (mAb) 73.3] with the CD8α hinge and transmembrane regions, and the human CD3ζ and 4-1BB activation domains. The transduced muFAP-CAR mouse T cells secreted IFN-γ and killed FAP-expressing 3T3 target cells specifically. Adoptively transferred 73.3-FAP-CAR mouse T cells selectively reduced FAPhi stromal cells and inhibited the growth of multiple types of subcutaneously transplanted tumors in wild-type, but not FAP-null immune-competent syngeneic mice. The antitumor effects could be augmented by multiple injections of the CAR T cells, by using CAR T cells with a deficiency in diacylglycerol kinase, or by combination with a vaccine. A major mechanism of action of the muFAP-CAR T cells was the augmentation of the endogenous CD8+ T-cell antitumor responses. Off-tumor toxicity in our models was minimal following muFAP-CAR T-cell therapy. In summary, inhibiting tumor growth by targeting tumor stroma with adoptively transferred CAR T cells directed to FAP can be safe and effective, suggesting that further clinical development of anti-human FAP-CAR is warranted. Cancer Immunol Res; 2(2); 154–66. ©2013 AACR.
Data from Granulin–Epithelin Precursor Renders Hepatocellular Carcinoma Cells Resistant to Natural Killer Cytotoxicity
Authors: Cheung Phyllis F.Y. , Yip Chi Wai , Wong Nicholas C.L. , Fong Daniel Y.T. , Ng Linda W.C. , Wan Angus M.Y. , Wong Chun Kwok , Cheung Tan To , Ng Irene O.L. , Poon Ronnie T.P. , Fan Sheung Tat , Cheung Siu Tim
Published: April 2023

Abstract
Immunoevasion is an emerging hallmark of cancer. Impairment of natural killer (NK) cytotoxicity is a mechanism to evade host immunosurveillance. Granulin–epithelin precursor (GEP) is a hepatic oncofetal protein regulating growth, invasion, and chemoresistance in hepatocellular carcinoma (HCC). We examined the role of GEP in conferring HCC cells the ability to evade NK cytotoxicity. In HCC cell lines, GEP overexpression reduced, whereas GEP suppression enhanced sensitivity to NK cytotoxicity. GEP downregulated surface expression of MHC class I chain–related molecule A (MICA), ligand for NK stimulatory receptor NK group 2 member D (NKG2D), and upregulated human leukocyte antigen-E (HLA-E), ligand for NK inhibitory receptor CD94/NKG2A. Functionally, GEP augmented production of soluble MICA, which suppressed NK activation. Matrix metalloproteinase (MMP)2 and MMP9 activity was involved partly in the GEP-regulated MICA shedding from HCC cells. In primary HCCs (n = 80), elevated GEP (P < 0.001), MICA (P < 0.001), and HLA-E (P = 0.089) expression was observed when compared with those in nontumor (n = 80) and normal livers (n = 10). Serum GEP (P = 0.010) and MICA (P < 0.001) levels were higher in patients with HCC (n = 80) than in healthy individuals (n = 30). High serum GEP and/or MICA levels were associated with poor recurrence-free survival (log-rank test, P = 0.042). Importantly, GEP blockade by mAbs sensitized HCC cells to NK cytotoxicity through MICA. In summary, GEP rendered HCC cells resistant to NK cytotoxicity by modulating MICA expression, which could be reversed by GEP blockade using antibody. Serum GEP and MICA levels are prognostic factors and can be used to stratify patients for targeted therapy. Cancer Immunol Res; 2(12); 1209–19. ©2014 AACR.
Data from GITR Agonism Enhances Cellular Metabolism to Support CD8+ T-cell Proliferation and Effector Cytokine Production in a Mouse Tumor Model
Authors: Sabharwal Simran S. , Rosen David B. , Grein Jeff , Tedesco Dana , Joyce-Shaikh Barbara , Ueda Roanna , Semana Marie , Bauer Michele , Bang Kathy , Stevenson Christopher , Cua Daniel J. , Zúñiga Luis A.
Published: April 2023

Abstract
GITR is a costimulatory receptor currently undergoing phase I clinical trials. Efficacy of anti-GITR therapy in syngeneic mouse models requires regulatory T-cell depletion and CD8+ T-cell costimulation. It is increasingly appreciated that immune cell proliferation and function are dependent on cellular metabolism. Enhancement of diverse metabolic pathways leads to different immune cell fates. Little is known about the metabolic effects of GITR agonism; thus, we investigated whether costimulation via GITR altered CD8+ T-cell metabolism. We found activated, GITR-treated CD8+ T cells upregulated nutrient uptake, lipid stores, glycolysis, and oxygen consumption rate (OCR) in vitro. Using MEK, PI3Kδ, and metabolic inhibitors, we show increased metabolism is required, but not sufficient, for GITR antibody (DTA-1)-induced cellular proliferation and IFNγ production. In an in vitro model of PD-L1–induced CD8+ T-cell suppression, GITR agonism alone rescued cellular metabolism and proliferation, but not IFNγ production; however, DTA-1 in combination with anti–PD-1 treatment increased IFNγ production. In the MC38 mouse tumor model, GITR agonism significantly increased OCR and IFNγ and granzyme gene expression in both tumor and draining lymph node (DLN) CD8+ T cells ex vivo, as well as basal glycolysis in DLN and spare glycolytic capacity in tumor CD8+ T cells. DLN in GITR-treated mice showed significant upregulation of proliferative gene expression compared with controls. These data show that GITR agonism increases metabolism to support CD8+ T-cell proliferation and effector function in vivo, and that understanding the mechanism of action of agonistic GITR antibodies is crucial to devising effective combination therapies. Cancer Immunol Res; 6(10); 1199–211. ©2018 AACR.
Data from Plasmacytoid Dendritic Cells Support Melanoma Progression by Promoting Th2 and Regulatory Immunity through OX40L and ICOSL
Authors: Aspord Caroline , Leccia Marie-Therese , Charles Julie , Plumas Joel
Published: April 2023

Abstract
Even though melanoma is considered to be one of the most immunogenic solid tumors, handling its development remains a challenge. The basis for such escape from antitumor immune control has not yet been documented. Plasmacytoid dendritic cells (pDC) are emerging as crucial but still enigmatic cells in cancer. In melanoma, the function of tumor-infiltrating pDCs remains poorly explored. We investigated the pathophysiologic role of pDCs in melanoma, both ex vivo from a large cohort of melanoma patients and in vivo in melanoma-bearing humanized mice. pDCs were found in high proportions in cutaneous melanoma and tumor-draining lymph nodes, yet associated with poor clinical outcome. We showed that pDCs migrating to the tumor microenvironment displayed particular features, subsequently promoting proinflammatory Th2 and regulatory immune profiles through OX40L and ICOSL expression. Elevated frequencies of interleukin (IL)-5-, IL-13- and IL-10–producing T cells in patients with melanoma correlated with high proportions of OX40L- and ICOSL-expressing pDCs. Strikingly TARC/CCL17, MDC/CCL22, and MMP-2 found in the melanoma microenvironment were associated with pDC accumulation, OX40L and ICOSL modulation, and/or early relapse. Thus, melanoma actively exploits pDC plasticity to promote its progression. By identifying novel insights into the mechanism of hijacking of immunity by melanoma, our study exposes potential for new therapeutic opportunities. Cancer Immunol Res; 1(6); 402–15. ©2013 AACR.