bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A82: Direct and indirect regulators of epithelial-to-mesenchymal transition mediated immunosuppression in breast carcinomas
Authors: Dongre Anushka , Rashidian Mohammad , Eaton Elinor Ng , Reinhardt Ferenc , Nepal Sunita , Ploegh Hidde , Weinberg Robert 
Published: March 2020

Abstract
The epithelial-to-mesenchymal transition (EMT) is a cell-biologic program that confers mesenchymal traits on carcinoma cells and drives their metastatic dissemination. We recently demonstrated that epithelial and mesenchymal carcinomas recruit distinct immune cells to their tumor microenvironments (TME) and differ in their susceptibility to checkpoint blockade. Specifically, mesenchymal tumors recruit immunosuppressive cells to their TME and are refractory to checkpoint blockade, while epithelial tumors recruit CD8+ T cells instead and are sensitive to checkpoint blockade. The mechanism(s) underlying such EMT-mediated immunosuppression remains elusive. Furthermore, the biologic relevance of various immune cells infiltrating epithelial versus mesenchymal tumors requires further understanding. Using a combination of novel epithelial and mesenchymal tumor models arising in syngeneic immunocompetent hosts combined with transcriptomic approaches, we demonstrate that mesenchymal but not epithelial tumors are specifically associated with an immunosuppressive gene signature. Furthermore, while CD8+ T cells play a critical role in regulating tumor progression and responses to checkpoint blockade in epithelial breast tumors, they do not do so in mesenchymal breast tumors. On the contrary, mesenchymal tumors recruit and rely on M2-macrophages to generate an immunosuppressive TME and mount refractory responses to checkpoint blockade. Finally, we demonstrate that mesenchymal tumors utilize a combination of carcinoma cell-intrinsic direct and indirect mechanism(s) to assemble an immunosuppressive TME. This work suggests that epithelial and mesenchymal breast carcinomas have dramatically different immunologic profiles. Thus, the residence of carcinoma cells in the epithelial or mesenchymal states can dictate their corresponding responses to checkpoint blockade immunotherapies. This in turn can therefore have a direct translational impact on breast cancer patients.
Citation Format: Anushka Dongre, Mohammad Rashidian, Elinor Ng Eaton, Ferenc Reinhardt, Sunita Nepal, Hidde Ploegh, Robert Weinberg. Direct and indirect regulators of epithelial-to-mesenchymal transition mediated immunosuppression in breast carcinomas [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A82.
Abstract A84: Clinical correlates and rationale for PEGylated adenosine deaminase 2 as a novel cancer immunotherapy
Authors: Saatci Ozge , Londoño Luz Marina , Clift Renee , Thompson Curt , LaBarre Mike , Sahin Ozgur , Cekic Caglar 
Published: March 2020

Abstract
Extracellular adenosine accumulates in solid tumors due to direct release or due to dephosphorylation of ATP, ADP, and AMP by extracellular enzymes such as CD39 and CD73. Adenosine signaling promotes metastasis and suppress antitumor immune responses. CD73 expression is associated with poor survival and chemotherapy resistance in triple-negative breast tumors. Adenosine deaminase 2 is a serum protein that catalyzes the deamination of adenosine to inosine. Expression of Adenosine deaminase 2 increases in pathologic conditions such as inflammation and cancer. Here we show that expression of the gene coding for ADA2 (CECR1) in lung and breast tumors is associated with increased expression of gene signatures associated with immune checkpoint blockade responsiveness. Our analyses have also indicated that increased ADA2 expression is associated with favorable outcomes among Her2+ and triple-negative breast cancer patients. Further stratification based on the expression of adenosine-generating enzymes, CD39/CD73, revealed that increased ADA2 expression is particularly associated with increased survival among patients with elevated CD39 and CD73 expression. ADA2 expression is found to be higher in stroma areas of the tumor as compared with tumor cells. Stromal expression but not tumor expression of ADA2 is associated with increased T-cell costimulation and infiltration scores. To support clinical evidence in preclinical models and to show the potential of PEGylated Adenosine Deaminase 2 (PEGADA2) as a novel therapy, we have shown that an engineered high-catalytic activity PEGADA2 variant (PEGADA2HCA) can slow growth of EMT6 syngeneic breast tumors. PEGADA2HCA also completely reversed adenosine inhibition of human T-cell activation. PEGADA2HCA treatment in humanized mice caused a linear dose-exposure relationship after repeat dosing. These results provide a strong rationale for testing PEGylated Adenosine Deaminase 2 alone or in combination in a clinical setting.
Citation Format: Ozge Saatci, Luz Marina Londoño, Renee Clift, Curt Thompson, Mike LaBarre, Ozgur Sahin, Caglar Cekic. Clinical correlates and rationale for PEGylated adenosine deaminase 2 as a novel cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A84.
Abstract A95: Neoantigen sequence similarity to pathogens and commensals determines immune phenotype of cancer samples and patient survival
Authors: Balogh Gergo Mihaly , Koncz Balazs , Asztalos Leo , Kemeny Lajos , Papp Balazs , Pal Csaba , Manczinger Mate 
Published: March 2020

Abstract
The immune system has to destroy pathogens and cancer, while tolerating commensal species and self-proteins. Neoantigens mediate the immune response against tumors. While tumors often carry many different neoantigens, the immune response is ineffective in a number of cases. Accordingly, only a small subset of neoantigens are immunogenic and are able to induce destructive responses. Why is it so? Numerous studies have shown that neoantigens similar to pathogens are more immunogenic. Recently, the role of the commensal flora in antitumor immunity has also come into research focus. We propose that molecular mimicry of cancer neoantigens to certain pathogenic as well as commensal species determines whether immune-mediated destruction or tolerance is formed. Consequently, the amino acid sequences of neoantigens in a given sample determine its immune phenotype and, thus, the survival of cancer patients. We analyzed cancer samples of The Cancer Genome Atlas. We identified neoantigens using established methods, and defined T cell-exposed motifs on neoantigen sequences. We determined the prevalence of these motifs in 1,303 commensal and 183 pathogen species. We report significant and relevant differences in the motif signature of cancer samples belonging to different immune subtypes: i) Inflammatory type samples carried numerous motifs of pathogens, while ii) TGF-beta dominant samples carried motifs of commensal bacteria and pathogens associated with immune suppression. At the same time, iii) neoantigens of immunologically quiet samples contained no or only a few motifs associated with pathogens or the microbiome. We clustered patients based on the motif signature of their cancer samples. Patients in different clusters showed significantly different survival. The effect of motif signature remained significant after controlling for patient demographics and missense mutation count in a Cox model. We conclude that neoantigen sequence signature determines the type of immune response against cancer cells and, thus, patient survival. These modified sequences are able to induce not only immune-mediated destruction, but also immune tolerance, which depends on its similarity to pathogen and commensal species.
Citation Format: Gergo Mihaly Balogh, Balazs Koncz, Leo Asztalos, Lajos Kemeny, Balazs Papp, Csaba Pal, Mate Manczinger. Neoantigen sequence similarity to pathogens and commensals determines immune phenotype of cancer samples and patient survival [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A95.
Abstract A96: Correlation of estrogen receptor beta with immune cells in colon cancer patients
Authors: Topi Geriolda , Lydrup Marie Louise , Sjölander Anita 
Published: March 2020

Abstract
Background: The estrogen receptor β (ERβ) is the predominant ER in the colon mucosa. We have previously reported that high expression of ERβ is independently associated with a better prognosis in patients with colorectal cancer (CRC), and the induction of this receptor in colon cancer cell lines resulted in upregulation of antitumorigenic proteins and downregulation of protumorigenic proteins. In addition, we have also shown that high mast cell density (MCD) was associated with longer survival of CRC patients.
Aim: To investigate the correlations between ERβ, mast cells (MCs), and prostaglandin D2 (PGD2) synthase.
Materials and Methods: A tissue microarray (TMA) of primary CRCs from 314 patients was stained for the expression of ERβ, MCs, and PGD2 synthase. Immunohistochemistry was used to evaluate the staining intensity by using the immunoreactive score (IRS).
Results: Patients with high ERβ expression had higher number of MCs, and there was a significant positive correlation between ERβ and MCs (r = 0.12, P = 0.03). In addition, patients with high ERβ expression had significantly higher activity of PGD synthase, which is produced mainly from MCs and is known to have antitumor effects. Furthermore, a strong, positive, and significant correlation was observed between ERβ expression and PGD synthase (r = 0.42, P &lt; 0.0001).
Future Plans: We aim to correlate the expression of ERβ with other immune cells and factors important for the tumor microenvironment, such are CD3+, CD8+, T-bet, and PDL-1.
Conclusion: High ERβ expression correlates with an antitumor immune prolife in CRC patients. This strengthens our hypothesis that the induction of ERβ expression in CRC patients will potentially improve the disease outcome.
Citation Format: Geriolda Topi, Marie Louise Lydrup, Anita Sjölander. Correlation of estrogen receptor beta with immune cells in colon cancer patients [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A96.
Abstract A98: Cancer-associated fibroblasts promote immunosuppression by inducing NOX2-expressing monocytic MDSCs in lung squamous cell carcinoma
Authors: Xiang Handan , Ramil Carlo , Hai Josephine , Zhang Chunsheng , Wang Huijun , Watkins Amanda A. , Afshar Roshi , Georgiev Peter , Song Xuelei , Sun Dongyu , Loboda Andrey , Jia Yanlin , Moy Lily Y , Chi An , Brandish Philip E. 
Published: March 2020

Abstract
Cancer-associated fibroblasts (CAFs) are activated fibroblasts that constitute the stromal component in the tumor microenvironment (TME). Although CAFs have been shown to promote tumor growth and mediate resistance to chemotherapy, their roles and potential mechanisms by which they may contribute to immune suppression in lung squamous cell carcinoma (LSCC) remain largely unexplored. Here, we identified a positive correlation between CAF and monocytic myeloid cell abundances in 501 primary LSCCs by mining the TCGA dataset. We further validated this finding in an independent cohort using imaging mass cytometry and found a significant spatial interaction between CAFs and monocytic myeloid cells in the TME. To delineate the interplay between CAFs and monocytic myeloid cells, we used chemotaxis assays to show that LSCC patient-derived CAFs promoted recruitment of CCR2+ monocytes via CCL2, which could be reversed by CCR2 inhibition. Using a three-dimensional culture system, we found that CAFs polarized monocytes to adopt a myeloid-derived suppressor cell (MDSC) phenotype characterized by robust suppression of autologous CD8+ T-cell proliferation and IFNγ production. To elucidate additional immunosuppressive mechanisms of CAF-educated MDSCs, we performed proteomic profiling and identified the NADPH oxidase 2 (NOX2) complex to be highly enriched in MDSCs. Pharmacologic inhibition of NOX2 activity in CAF-induced MDSCs restored CD8+ T-cell proliferation. Taken together, our study highlights a pivotal role of CAFs in regulating monocyte recruitment and differentiation and demonstrates that NOX2 inhibition abrogates the CAF-MDSC axis, illuminating a potential therapeutic path to reversing the CAF-mediated immunosuppressive microenvironment.
Citation Format: Handan Xiang, Carlo Ramil, Josephine Hai, Chunsheng Zhang, Huijun Wang, Amanda A. Watkins, Roshi Afshar, Peter Georgiev, Xuelei Song, Dongyu Sun, Andrey Loboda, Yanlin Jia, Lily Y Moy, An Chi, Philip E. Brandish. Cancer-associated fibroblasts promote immunosuppression by inducing NOX2-expressing monocytic MDSCs in lung squamous cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A98.
Abstract B104: Immunomodulatory effect of 15-hydroxy prostaglandin dehydrogenase in colon cancer
Authors: Satapathy Shakti R. , Sjolander Anita 
Published: March 2020

Abstract
Cyclooxygenase-2, the key player in the biosynthesis of prostaglandin-E2 (PGE2) is often upregulated in colon cancer. In addition, TNF-α, the prime regulator of COX-2 and mPGES-1, also contributes to increased synthesis of PGE2. However, 15-hydroxy prostaglandin dehydrogenase, a tumor suppressor playing major role in PGE2 catabolism, is often downregulated in colon cancer. Interestingly, colon cancer patients expressing high levels of cysteinyl leukotriene receptor-2 (CysLT2R) show good prognosis and therefore, we investigated a potential link between CysLT2R-signaling and 15-PGDH in metastatic colon cancer. Elevation of 15-PGDH expression by LTC4, a CysLT2R ligand, exhibited antitumor activity in colon cancer cells with significant phosphorylation of β-catenin with concurrent activation of CASPASE-3 and dramatic downregulation of TNF-α as well as NFκβ1 mRNA expression in HT-29 and Caco-2 colon cancer cells. The interaction between programmed death ligand 1 (PD-L1) and programmed death receptor 1 (PD-1) of cancer cells and T cells, respectively, leads to T-cell inactivation and tumor escape. We observed that recombinant TNF-α stimulated colon cancer cells expressed high PD-L1 compared to the unstimulated counterparts, which was downregulated by LTC4 treatment. Protumorigenic role and association of tumor-associated macrophage (TAMs) with PD-L1 was also evident with increase in CD-47 mRNA expression. Human (SW480, SW620) and mouse (MC-38) colon cancer cells exposed to conditioned media of chemically differentiated THP-1 and RAW 264.7 cells, respectively, showed abundant expression of PD-L1 in both mRNA and protein level along with CD-47 in mRNA level, which was inhibited by LTC4 stimulation via activation of CysLT2R in a 15-PGDH dependent manner. Hence restoration of 15-PGDH expression through CysLT2R-signaling promotes immunomodulatory effect, indicating a promising therapeutic alternative for metastatic colon cancer with high TAM infiltration.
Citation Format: Shakti R. Satapathy, Anita Sjolander. Immunomodulatory effect of 15-hydroxy prostaglandin dehydrogenase in colon cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B104.
Abstract B13: Immunogenic chemotherapy alters microbiome-induced T-cell activation
Authors: Smith Peter L. , Dalgleish A.G. 
Published: March 2020

Abstract
Introduction: The efficacy of cancer immunotherapy is influenced by the patient’s intestinal microbiome. The local and systemic effects of the microbiome on immune function are thought to depend upon a combination of microbial metabolites produced collectively from the diverse bacterial species present in the intestine and the activation of intestine-resident immunocytes such as antigen-presenting cells and T lymphocytes. The interactions between the microbiome and the immune response are regulated by Intestinal epithelial cells, which together maintain intestinal immune homeostasis. The oral chemotherapeutics lenalidomide (Len) and cyclophosphamide (CP) are currently licensed for the treatment of numerous cancers. These agents are also potent immune modulators and have been studied alongside checkpoint inhibition (CPI) with promising results. Few studies have sought to investigate the effect of these immune-modulatory agents on immune responses activated by the intestinal microbiome. In this study the immunomodulatory properties of low-dose Len and CP on IEC function and T-cell activation were investigated in combination with microbial TLR ligands and short-chain fatty acids (SFCA), immunogenic metabolites produced by intestinal bacteria.
Results: Both Len and CP altered cytokine expression from IEC in response to stimulation by TLR ligands including lipopolysaccharide, peptidoglycan, and flagellin. Combinations of SCFA modulated the viability and proinflammatory effects of CP on IEC. SCFA and LEN in combination enhanced the expression of antimicrobial peptides from IEC. LEN enhanced IFN-γ and IL-17A expression by CD8+ and CD4+ T-cells. Combinations of LEN and the SCFA acetate further enhanced IFN-γ and IL-17A expression. Cytokines expressed by IEC predispose towards the development of Th2 immune responses; however, in the presence of IEC expressed Th2 skewing cytokines including IL-33 and TSLP, LEN promoted IFN-γ expressing Th1 responses. CP inhibited the ability of the SCFA butyrate to induce T-regulatory cells while Len mitigated the Th1 inhibitory effect of butyrate.
Conclusions: LEN and SCFA synergize to drive Th1 responses while CP mitigate their immune-regulatory properties. Both LEN and CP prime IEC function. Collectively these data provide evidence supporting the ability of low-dose LEN and CP to alter components of intestinal immune network consisting of IEC, Immunocytes, and the microbiome. These findings have implications for the homeostasis of intestinal immunity and the maintenance of the intestinal microbiome during chemotherapeutic treatment. The influence of these agents on the microbiome and CPI immunotherapy is under investigation.
Citation Format: Peter L. Smith, A.G. Dalgleish. Immunogenic chemotherapy alters microbiome-induced T-cell activation [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B13.
Abstract B2: Coexpression of effector T cell-associated chemokine receptors defines T-cell subsets with different roles in antitumor response and toxicity of dual checkpoint blockade
Authors: Gonzales Rodney J.M. Macedo , Harle David , Wang Ximi K. , Matschiner Alexandra , Reshef Ran 
Published: March 2020

Abstract
Dual checkpoint blockade has yielded impressive clinical responses in cancer treatment, but only a subset of patients responds and immune-related adverse events (irAE) are common, frequently leading to treatment discontinuation. Both CCR5 and CXCR3 expression are associated with effector T-cell trafficking and favorable outcomes in various tumors, but only CXCR3 was shown to exhibit a nonredundant role for cytotoxic T-cell trafficking across tumor vessels, while CCR5 has been implicated in recruitment of regulatory T cells to the tumor microenvironment. Here, we explored the coexpression of T cell-associated chemokine receptors in human melanoma and studied the effect of genetic and pharmacologic manipulation of CCR5 on PD-1/CTLA-4 (P1C4) blockade efficacy and toxicity observed in B16 tumor-bearing mice. We found that in human melanoma CCR5 and CXCR3 expression characterizes different T-cell subsets based on their coexpression with other chemokine receptors at the single-cell level. These subsets exhibit distinct phenotypic and functional characteristics in blood and tumor; CXCR3 indicated less differentiated T cells with greater proliferative potential while CCR5 expression was more abundant on terminal effector cells. In addition, subsets expressing only CXCR3 were increased in patients who received checkpoint blockade while subsets that express CCR5 were unaffected by the treatment. In murine melanoma, dual checkpoint inhibition using PD-1/CTLA-4 blockade significantly increased CXCR3, but not CCR5 expression on T cells. Moreover, a murine model of PD-1/CTLA-4 blockade-induced irAE showed high levels of CCR5+ T cells in toxicity target organs. When PD-1/CTLA-4 inhibitors were administered to either CCR5-KO mice or WT mice treated with the CCR5 antagonist maraviroc, there was a significant decrease in tumor growth and improved survival compared to WT mice receiving P1C4 alone. Together these results reveal distinct, potentially opposite roles for CCR5 and CXCR3 subsets specifically in the setting of dual checkpoint blockade, that can be redirected to improve efficacy and reduce toxicity observed in melanoma.
Citation Format: Rodney J.M. Macedo Gonzales, David Harle, Ximi K. Wang, Alexandra Matschiner, Ran Reshef. Coexpression of effector T cell-associated chemokine receptors defines T-cell subsets with different roles in antitumor response and toxicity of dual checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B2.