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The tumor immune microenvironment is a main contributor to cancer progression and a promising therapeutic target for oncology. However, immune microenvironments vary profoundly between patients, and biomarkers for prognosis and treatment response lack precision. A comprehensive compendium of tumor immune cells is required to pinpoint predictive cellular states and their spatial localization. We generated a single-cell tumor immune atlas, jointly analyzing published data sets of >500,000 cells from 217 patients and 13 cancer types, providing the basis for a patient stratification based on immune cell compositions. Projecting immune cells from external tumors onto the atlas facilitated an automated cell annotation system. To enable in situ mapping of immune populations for digital pathology, we applied SPOTlight, combining single-cell and spatial transcriptomics data and identifying colocalization patterns of immune, stromal, and cancer cells in tumor sections. We expect the tumor immune cell atlas, together with our versatile toolbox for precision oncology, to advance currently applied stratification approaches for prognosis and immunotherapy. ; This publication is part of a project (BCLLATLAS) that has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No. 810287). This work has received funding from the Ministerio de Ciencia, Innovación y Universidades (SAF2017-89109-P; AEI/FEDER, UE) and the Fundació La Marató de TV3 (201903-30-31-32).We further acknowledge funding from the St. Vincent's Clinic Foundation (V.T.C.) and the National Health and Medical Research Council Investigator Grant (APP1175781, J.E.P.), the Fundación Asociación Española contra el Cáncer (AECC), FERO (EDM), Ramón Areces Foundation, Cellex Foundation, BBVA (CAIMI), the ISCIII, FIS (PI16/01278), Juan de la Cierva formación fellowship (C.R.-P.) and Sara Borrell fellowship (E.P.-R.). Core funding is from the ISCIII and the Generalitat de Catalunya. We acknowledge support of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership, the Centro de Excelencia Severo Ochoa, the CERCA Programme / Generalitat de Catalunya, the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) through the nstituto de Salud Carlos III and the Generalitat de Catalunya through Departament de Salut and Departament d'Empresa i Coneixement. We also acknowledge the cofinancing by the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) with funds from the European Regional Development Fund (ERDF) corresponding to the 2014–2020 Smart Growth Operating Program

In the last years, the rediscovery of the Warburg effect and high tumoral glutaminolysis has lead to a renewed interest in cancer metabolism. Moreover, recent studies have put some importance in endothelial cells metabolism. Inquiring into the metabolism of accompanying cells of the tumor microenvironment, such as endothelial and immune cells, could shed some light in the search for alternative cancer therapeutic approaches. In this work the use of glucose, glutamine and palmitate as metabolic fuels by endothelial and tumoral cells is studied. In addition, we also test if two antiangiogenic compounds previously described by our group are able to modify key steps of endothelial and/or tumor cells metabolism ; [Our experimental work is supported by grants BIO2014-56092-R (MINECO and FEDER) and P12-CTS-1507 (Andalusian Government and FEDER) and funds from group BIO-267 (Andalusian Government). The "CIBER de Enfermedades Raras" is an initiative from the ISCIII (Spain)]. This communicaction has the support of a travel grant Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Yi Feng,1,2 Ying Dai,1,2 Zhihua Gong,1,2 Jia-Nan Cheng,1,2 Longhui Zhang,1,2 Chengdu Sun,1,2 Xianghua Zeng,1,2 Qingzhu Jia,1,2 Bo Zhu1,2 1Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, People's Republic of China; 2Chongqing Key Laboratory of Tumor Immunotherapy, Chongqing, People's Republic of China Background: A suppressive immune microenvironment and pathological angiogenesis are hallmarks of gastric cancer. Theoretically, immune checkpoint inhibitors (ICIs) stimulate pre-primed neoantigen-specific T cells, and antiangiogenic agents then facilitate their infiltration into the tumor niche by promoting vascular normalization. Currently, the interconnections of these two phenotypes and their relevance to the tumor microenvironment (TME) have not been fully characterized in gastric cancer.Materials and methods: Transcriptome profiling data retrieved from The Cancer Genome Atlas (TCGA) database were used to deconvolute the feature of TME for gastric cancer (N = 375). Machine learning, correlation, and prognosis analysis were applied to elucidate the correlations between angiogenesis, cytotoxic T lymphocyte infiltration, and patient survival.Results: Substantial heterogeneous infiltration of immune cell populations among cases was observed. Furthermore, among targetable pathways, angiogenesis was identified as the dominant factor in discriminating different infiltration statuses. Most importantly, the angiogenesis pathway was negatively correlated with the amount of activated CD8+ T cells only for patients with a higher infiltration, and the concomitance of low angiogenesis signaling and highly activated CD8+ T-cell infiltration was associated with a significant survival benefit.Conclusion: Our findings demonstrated a negative correlation between angiogenesis signaling and cytotoxic function in gastric cancer patients with a highly infiltrated immune niche. These data provided a rationale for potential combination strategy and further clinical investigations of ICIs plus antiangiogenesis agents for patients with gastric cancer with an inflamed TME. Keywords: gastric cancer, immune microenvironment, TCGA, angiogenesis, therapeutic implications

Signals from the tumor microenvironment (TME) have a profound influence on the maintenance and progression of cancers. Chronic inflammation and the infiltration of immune cells in breast cancer (BC) have been strongly associated with early carcinogenic events and a switch to a more immunosuppressive response. Cancer-associated fibroblasts (CAFs) are the most abundant stromal component and can modulate tumor progression according to their secretomes. The immune cells including tumor-infiltrating lymphocytes (TILs) (cytotoxic T cells (CTLs), regulatory T cells (Tregs), and helper T cell (Th)), monocyteinfiltrating cells (MICs), myeloid-derived suppressor cells (MDSCs), mast cells (MCs), and natural killer cells (NKs) play an important part in the immunological balance, fluctuating TME between protumoral and antitumoral responses. In this review article, we have summarized the impact of these immunological players together with CAF secreted substances in driving BC progression. We explain the crosstalk of CAFs and tumor-infiltrating immune cells suppressing antitumor response in BC, proposing these cellular entities as predictive markers of poor prognosis. CAF-tumor-infiltrating immune cell interaction is suggested as an alternative therapeutic strategy to regulate the immunosuppressive microenvironment in BC. ; Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) CONICYT FONDECYT 11190990 3190931 National Commission for Scientific and Technological Research REDES Chile 180134 Thailand Science Research and Innovation, National Research Council of Thailand (NRCT), Ministry of Higher Education, Science, Research and Innovation Thailand RSA6280091 Faculty of Medicine Siriraj Hospital, Mahidol University R016033015 ANID (National Research and Development Agency from the Chilean Government; Program of International Cooperation to Support for the Formation of International Networks between Research Centers) 180134 ; Versión publicada - versión final del editor

In the recent years, the "tumor microenvironment" has been receiving growing attention due to its involvement in neoplastic transformation, tumor growth, invasion, and protection of tumor cells from host immune response. All these events are facilitated by chemical signals produced by the tumor as well as the surrounding stromal cells. This review is divided into two main parts in which the first part discusses the receptor tyrosine kinase (RTK)-mediated growth factor signaling, steroid hormone (SH) signaling, ancient signaling pathways, and other molecules that are involved in tumorigenesis and how they interact with each other to create a complex tumor microenvironment. In the second part, we bring together the recent nanocarrier-mediated drug delivery approaches to target the signaling pathways/molecules present in the tumor microenvironment. ; Foundation for Science and Technology (FCT) [(SFRH/BPD/89493/2012]; FCT [SFRH/BD/72809/2010]; Portuguese Government; FCT national funds (PIDDAC) [PTDC/AGR-GPL/119211/2010, PEst-C/AGR/UI4033/2011]; European Fund for Regional Development (FEDER) through COMPETE Operational Programme Competitive Factors (POFC) ; info:eu-repo/semantics/publishedVersion

The tumor microenvironment exhibits altered metabolic properties as a consequence of the needs of tumor cells, the natural selection of the most adapted clones, and the selfish relationship with other cell types. Beyond its role in supporting uncontrolled tumor growth, through energy and building materials obtention, metabolism is a key element controlling tumor immune evasion. Immunotherapy has revolutionized the treatment of cancer, being the first line of treatment for multiple types of malignancies. However, many patients either do not benefit from immunotherapy or eventually relapse. In this review we overview the immunoediting process with a focus on the metabolism-related elements that are responsible for increased immune evasion, either through reduced immunogenicity or increased resistance of tumor cells to the apoptotic action of immune cells. Finally, we describe the main molecules to modulate these immune evasion processes through the control of the metabolic microenvironment as well as their clinical developmental status ; Work in the authors' laboratories was supported by "Instituto de Salud Carlos III" (ISCIII) PI19/01652 grant, Ministry of Science and Innovation RTC2017-6502-1 INmunoSIGHT and European Union's Horizon 2020 research and innovation programme, CLARIFY 875160 grant, to M.P. A.C.-B. received a Spanish Lung Cancer Group (SLCG) grant and is supported by a ISCIII-"Sara Borrell" contract CD19/00170. M.C. is supported by PEJD-2019-PRE/BMD-17006 contract granted to A.C.-B. R.L.-B. was supported by PEJ16/MED/AI-1972 and PEJD-2018-PRE/SAL-8641 from European Social Fund and Comunidad de Madrid, both granted to M.P