Oncology
Abstract
Immune checkpoint blockade has revolutionized cancer treatment. Patients developing immune mediated adverse events, such as colitis, appear to particularly benefit from immune checkpoint inhibition. Yet, the contributing mechanisms are largely unknown. We identified a systemic LPS signature in melanoma patients with colitis following anti–cytotoxic T lymphocyte–associated antigen 4 (anti–CTLA-4) checkpoint inhibitor treatment and hypothesized that intestinal microbiota–derived LPS contributes to therapeutic efficacy. Because activation of immune cells within the tumor microenvironment is considered most promising to effectively control cancer, we analyzed human and murine melanoma for known sentinels of LPS. We identified mast cells (MCs) accumulating in and around melanomas and showed that effective melanoma immune control was dependent on LPS-activated MCs recruiting tumor-infiltrating effector T cells by secretion of CXCL10. Importantly, CXCL10 was also upregulated in human melanomas with immune regression and in patients with colitis induced by anti–CTLA-4 antibody. Furthermore, we demonstrate that CXCL10 upregulation and an MC signature at the site of melanomas are biomarkers for better patient survival. These findings provide conclusive evidence for a “Trojan horse treatment strategy” in which the plasticity of cancer-resident immune cells, such as MCs, is used as a target to boost tumor immune defense.
Authors
Susanne Kaesler, Florian Wölbing, Wolfgang Eberhard Kempf, Yuliya Skabytska, Martin Köberle, Thomas Volz, Tobias Sinnberg, Teresa Amaral, Sigrid Möckel, Amir Yazdi, Gisela Metzler, Martin Schaller, Karin Hartmann, Benjamin Weide, Claus Garbe, Hans-Georg Rammensee, Martin Röcken, Tilo Biedermann
Abstract
Transcriptomic profiling classifies pancreatic ductal adenocarcinoma (PDAC) into several molecular subtypes with distinctive histological and clinical characteristics. However, little is known about the molecular mechanisms that define each subtype and their correlation with clinical outcome. Mutant KRAS is the most prominent driver in PDAC, present in over 90% of tumors, but the dependence of tumors on oncogenic KRAS signaling varies between subtypes. In particular, squamous subtype are relatively independent of oncogenic KRAS signaling and typically display much more aggressive clinical behavior versus progenitor subtype. Here, we identified that YAP1 activation is enriched in the squamous subtype and associated with poor prognosis. Activation of YAP1 in progenitor subtype cancer cells profoundly enhanced malignant phenotypes and transformed progenitor subtype cells into squamous subtype. Conversely, depletion of YAP1 specifically suppressed tumorigenicity of squamous subtype PDAC cells. Mechanistically, we uncovered a significant positive correlation between WNT5A expression and the YAP1 activity in human PDAC, and demonstrated that WNT5A overexpression led to YAP1 activation and recapitulated YAP1-dependent but Kras-independent phenotype of tumor progression and maintenance. Thus, our study identifies YAP1 oncogene as a major driver of squamous subtype PDAC and uncovers the role of WNT5A in driving PDAC malignancy through activation of the YAP pathway.
Authors
Bo Tu, Jun Yao, Sammy Ferri-Borgogno, Jun Zhao, Shujuan Chen, Qiuyun Wang, Liang Yan, Xin Zhou, Cihui Zhu, Seungmin Bang, Qing Chang, Christopher A. Bristow, Ya'an Kang, Hongwu Zheng, Huamin Wang, Jason B. Fleming, Michael Kim, Timothy P. Heffernan, Giulio F. Draetta, Duojia Pan, Anirban Maitra, Wantong Yao, Sonal Gupta, Haoqiang Ying
Efficient ADCC- killing of meningioma by avelumab and a high-affinity natural killer cell line, haNK
Abstract
Meningiomas are the most common adult primary tumor of the central nervous system, but there are no known effective medical therapies for recurrent meningioma, particularly for WHO grade II and III tumors. Meningiomas arise from the meninges, located outside the blood-brain barrier, and therefore may be directly targeted by antibody-mediated immunotherapy. We found that PD-L1 was highly expressed in multiple human malignant meningioma cell lines and patient tumor samples. PD-L1 was targeted with the anti-PD-L1 antibody avelumab and directed natural killer cells to mediate antibody-dependent cellular cytotoxicity (ADCC) of PD-L1-expressing meningioma tumors both in vitro and in vivo. ADCC of meningioma cells was significantly increased in target cells that upregulated PD-L1 expression and, conversely, abrogated in tumor cells that were depleted of PD-L1. Additionally, the high-affinity natural killer cell line, haNK, outperformed healthy donor NK cells in meningioma ADCC. Together, these data support a clinical trial designed to target PD-L1 with avelumab and haNK cells, potentially offering a novel immunotherapeutic approach for patients with malignant meningioma.
Authors
Amber J. Giles, Shuyu Hao, Michelle R. Padget, Hua Song, Wei Zhang, John Lynes, Victoria E. Sanchez, Yang Liu, Jinkyu Jung, Xiaoyu Cao, Rika Fujii, Randy L. Jensen, David Gillespie, Jeffrey Schlom, Mark R. Gilbert, Edjah K. Nduom, Chunzhang Yang, John H. Lee, Patrick Soon-Shiong, James W. Hodge, Deric M. Park
Abstract
Aberrant activation of the NF-κB transcription factors underlies chemoresistance in various cancer types including colorectal cancer (CRC). Targeting the activating mechanisms, particularly with inhibitors to the upstream IκB kinase (IKK) complex, is a promising strategy to augment the effect of chemotherapy. However, clinical success has been limited largely due to low specificity and toxicities of tested compounds. In solid cancers, the IKK kinases is driven predominantly by the Toll-like/Interlekin-1 receptor family members, which signal through the Interleukin-1 Receptor-Associated Kinases (IRAKs), with isoform 4 (or IRAK4) being the most critical. The pathogenic role and therapeutic value of IRAK4 in CRC has not been investigated. We found that IRAK4 inhibition significantly abrogates colitis-induced neoplasm in APCMin/+ mice, and bone marrow transplant experiments showed an essential role of IRAK4 in immune cells during neoplastic progression. Chemotherapy significantly enhances IRAK4 and NF-κB activity in CRC cells through upregulating TLR9 expression, which can in turn be suppressed by IRAK4 and IKK inhibitors, suggesting a feedforward pathway that protects CRC cells from chemotherapy. Lastly, increased tumor phospho-IRAK4 staining or IRAK4 mRNA expression are associated with significantly worse survival in CRC patients. Our results support targeting IRAK4 to improve the effects of chemotherapy and outcomes in CRC.
Authors
Qiong Li, Yali Chen, Daoxiang Zhang, Julie Grossman, Lin Li, Namrata Khurana, Hongmei Jiang, Patrick Grierson, John Herndon, David G. DeNardo, Grant A. Challen, Jingxia Liu, Marianna B. Ruzinova, Ryan C. Fields, Kian-Huat Lim
Abstract
Clinical trials of high-dose androgen therapy for prostate cancer have shown promising efficacy but are limited by lack of criteria to identify likely responders. To elucidate factors that govern the growth-repressive effects of high-dose androgens we applied an unbiased integrative approach utilizing genetic screens and transcriptional profiling of prostate cancer cells with or without demonstrated phenotypic sensitivity to androgen-mediated growth repression. Through this comprehensive analysis, we identified genetic events and related signaling networks that determine the response to both high-dose androgen and androgen withdrawal. We applied these findings to develop a gene signature that may serve as an early indicator of treatment response and identify men with tumors amenable to high dose androgen therapy.
Authors
Michael D. Nyquist, Alexandra Corella, Osama Mohamad, Ilsa Coleman, Arja Kaipainen, Daniel A. Kuppers, Jared M. Lucas, Patrick J. Paddison, Stephen R. Plymate, Peter S. Nelson, Elahe A. Mostaghel
Abstract
CD8+ tumor-infiltrating lymphocytes (TILs) correlate with relapse-free survival (RFS) in most cancer types, including breast cancer. However, subset composition, functional status, and spatial location of CD8+ TILs in relation to RFS in human breast tumors remain unclear. Spatial tissue analysis via quantitative immunofluorescence showed that infiltration of CD8+ T cells into cancer islands is more significantly associated with RFS than CD8+ T cell infiltration into either tumor stroma or total tumor. Localization into cancer islands within tumors is mediated by expression of the integrin CD103, which is a marker for tissue resident memory T cells (TRMs). Analysis of fresh tumor samples revealed that CD8+ TRMs are functionally similar to other CD8+ TILs, suggesting that the basis of their protective effect is their spatial distribution rather than functional differences. Indeed, CD103+ TRMs, as compared to CD103- CD8+ TILs, are enriched within cancer islands and CD8+ TRM proximity to cancer cells drives the association of CD8+ TIL densities with RFS. Together, these findings reveal the importance of cancer island localized CD8+ TRMs in surveillance of the breast tumor microenvironment and as a critical determinant of RFS in breast cancer patients.
Authors
Colt A. Egelston, Christian Avalos, Travis Y. Tu, Anthony Rosario, Roger Wang, Shawn Solomon, Gayathri Srinivasan, Michael S. Nelson, Yinghui Huang, Min Hui Lim, Diana L. Simons, Ting-Fang He, John H. Yim, Laura Kruper, Joanne Mortimer, Susan Yost, Weihua Guo, Christopher Ruel, Paul H. Frankel, Yuan Yuan, Peter P. Lee
Abstract
Solid tumors impose immunological and physical barriers to the efficacy of chimeric antigen receptor (CAR) T-cell therapy that are not reflected in conventional pre-clinical testing against singularized tumor cells in two-dimensional culture. Here, we established microphysiologic three-dimensional (3D) lung and breast cancer models that resemble architectural and phenotypical features of primary tumors, and evaluated the anti-tumor function of ROR1-specific CAR T-cells. 3D tumors were established from A549 (non-small cell lung cancer) and MDA-MB-231 (triple-negative breast cancer) cell lines on a biological scaffold with intact basement membrane (BM) under static and dynamic culture conditions, which resulted in progressively increasing cell mass and invasive growth phenotype (dynamic>static; MDA-MB-231>A549). Treatment with ROR1-CAR T-cells conferred potent anti-tumor effects. In dynamic culture, CAR T-cells actively entered arterial medium flow, adhered to and infiltrated the tumor mass. ROR1-CAR T-cells penetrated deep into tumor tissue and eliminated multiple layers of tumor cells located above and below the BM. The microphysiologic 3D tumor models developed in this study are standardized scalable test systems that can be used either in conjunction with or in lieu of animal testing to interrogate the anti-tumor function of CAR T-cells, and to obtain proof-of-concept for their safety and efficacy prior to clinical application.
Authors
Lars Wallstabe, Claudia Göttlich, Lena C. Nelke, Johanna Kühnemundt, Thomas Schwarz, Thomas Nerreter, Hermann Einsele, Heike Walles, Gudrun Dandekar, Sarah L. Nietzer, Michael Hudecek
Abstract
BACKGROUND. Aberrant expression of RNA processing genes may drive the alterative RNA profile in lower-grade gliomas (LGGs). Thus, we aimed to further stratify LGGs based on the expression of RNA processing genes. METHODS. This study included 446 LGGs from The Cancer Genome Atlas (TCGA, training set) and 171 LGGs from the Chinese Glioma Genome Atlas (CGGA, validation set). The least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was conducted to develop a risk-signature. The receiver operating characteristic (ROC) curves and Kaplan–Meier curves were used to study the prognosis value of the risk-signature. RESULTS. Among the tested 784 RNA processing genes, 276 were significantly correlated with the OS of LGGs. Further LASSO Cox regression identified a 19-gene risk-signature, whose risk score was also an independently prognosis factor (P<0.0001, multiplex Cox regression) in the validation dataset. The signature had better prognostic value than the traditional factors “age”, “grade” and “WHO 2016 classification” for 3‐ and 5‐year survival both two datasets (AUCs > 85%). Importantly, the risk-signature could further stratify the survival of LGGs in specific subgroups of WHO 2016 classification. Furthermore, alternative splicing events for genes such as EGFR and FGFR were found to be associated with the risk score. mRNA expression levels for genes, which participated in cell proliferation and other processes, were significantly correlated to the risk score. CONCLUSIONS. Our results highlight the role of RNA processing genes for further stratifying the survival of patients with LGGs and provide insight into the alternative splicing events underlying this role.
Authors
Rui-Chao Chai, Yi-Ming Li, Ke-Nan Zhang, Yu-Zhou Chang, Yu-Qing Liu, Zheng Zhao, Zhi-Liang Wang, Yuan-Hao Chang, Guan-Zhang Li, Kuan-Yu Wang, Fan Wu, Yong-Zhi Wang
Abstract
Tumor-infiltrating B-cells (TIL-B) in breast cancer (BC) have previously been associated with improved clinical outcomes; however, their role(s) in tumor immunity is not currently well known. This study confirms and extends the correlation between higher TIL-B densities and positive outcomes through an analysis of HER2-positive and triple-negative BC patients from the BIG 02-98 clinical trial (10yr mean follow-up). Fresh tissue analyses identify an increase in TIL-B density in untreated primary BC compared to normal breast tissues, which is associated with global, CD4+ and CD8+ TIL, higher tumor grades, higher proliferation and hormone receptor negativity. All B-cell differentiation stages are detectable but significant increases in memory TIL-B are consistently present. BC with higher infiltrates are specifically characterized by germinal center TIL-B, which in turn are correlated with TFH TIL and antibody-secreting TIL-B principally located in tertiary lymphoid structures. Some TIL-B also interact directly with tumor cells. Functional analyses reveal TIL-B are responsive to BCR stimulation ex vivo, express activation markers and produce cytokines and immunoglobulins despite reduced expression of the antigen-presenting molecules HLA-DR and CD40. Overall, these data support the concept that ongoing humoral immune responses are generated by TIL-B and help to generate effective anti-tumor immunity at the tumor site.
Authors
Soizic Garaud, Laurence Buisseret, Cinzia Solinas, Chunyan Gu-Trantien, Alexandre de Wind, Gert Van den Eynden, Celine Naveaux, Jean-Nicolas Lodewyckx, Anaïs Boisson, Hugues Duvillier, Ligia Craciun, Lieveke Ameye, Isabelle Veys, Marianne Paesmans, Denis Larsimont, Martine Piccart-Gebhart, Karen Willard-Gallo
Abstract
Despite the propensity for gastric and esophageal adenocarcinomas to select for recurrent missense mutations in TP53, the precise functional consequence of these mutations remains unclear. Here we report that endogenous mRNA and protein levels of mutant p53 were elevated in cell lines and patients with gastric and esophageal cancer. Functional studies showed that mutant p53 was sufficient, but not necessary, for enhancing primary tumor growth in vivo. Unbiased genome-wide transcriptome analysis revealed that hypoxia signaling was induced by mutant p53 in 2 gastric cancer cell lines. Using real-time in vivo imaging, we confirmed that hypoxia reporter activity was elevated during the initiation of mutant p53 gastric cancer xenografts. Further investigation revealed that, like mutant p53, the HIF1/ARNT hypoxia pathway was not required for the primary tumor functions of advanced mutant p53 gastric cancer. These findings indicate that recurrent p53 mutations in gastroesophageal adenocarcinoma are unlikely to serve as effective therapeutic targets in advanced cancer. However, in elucidating the contribution of missense mutant p53 and hypoxia signaling, the results suggest hypotheses regarding how these recurrent genomic events may contribute to gastric and esophageal adenocarcinoma formation.
Authors
Nilay Sethi, Osamu Kikuchi, James McFarland, Yanxi Zhang, Max Chung, Nicholas Kafker, Mirazul Islam, Benjamin Lampson, Abhishek Chakraborty, William G. Kaelin Jr., Adam J. Bass
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