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The inflammatory microenvironment has been shown to play important roles in various stages of tumor development including initiation, growth, and metastasis. The inflammasome is a critical innate immune pathway for the production of active IL-1β, a potent inflammatory cytokine. Although inflammasomes are essential for host defense against pathogens and contribute to autoimmune diseases, their role in tumor progression remains controversial. Here, our results demonstrate that the inflammasome and IL-1β pathway promoted tumor growth and metastasis in animal and human breast cancer models. We found that tumor progression was associated with the activation of inflammasome and elevated levels of IL-1β at primary and metastatic sites. Mice deficient for inflammasome components exhibited significantly reduced tumor growth and lung metastasis. Furthermore, inflammasome activation promoted the infiltration of myeloid cells such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) into tumor microenvironments. Importantly, blocking IL-1R with IL-1R antagonist (IL-Ra) inhibited tumor growth and metastasis accompanied by decreased myeloid cell accumulation. Our results suggest that targeting the inflammasome/IL-1 pathway in tumor microenvironments may provide a novel approach for the treatment of cancer.

Immunotherapies such as immune checkpoint blockade (ICB) and adoptive cell therapy (ACT) have revolutionized cancer treatment, especially in patients whose disease was otherwise considered incurable. However, primary and secondary resistance to single agent immunotherapy often results in treatment failure, and only a minority of patients experience long-term benefits. This review article will discuss the relationship between cancer immune response and mechanisms of resistance to immunotherapy. It will also provide a comprehensive review on the latest clinical status of combination therapies (e.g., immunotherapy with chemotherapy, radiation therapy and targeted therapy), and discuss combination therapies approved by the US Food and Drug Administration. It will provide an overview of therapies targeting cytokines and other soluble immunoregulatory factors, ACT, virotherapy, innate immune modifiers and cancer vaccines, as well as combination therapies that exploit alternative immune targets and other therapeutic modalities. Finally, this review will include the stimulating insights from the 2020 China Immuno-Oncology Workshop co-organized by the Chinese American Hematologist and Oncologist Network (CAHON), the China National Medical Product Administration (NMPA) and Tsinghua University School of Medicine.

Single-cell multi-omics (scMulti-omics) allows the quantification of multiple modalities simultaneously to capture the intricacy of complex molecular mechanisms and cellular heterogeneity. Existing tools cannot effectively infer the active biological networks in diverse cell types and the response of these networks to external stimuli. Here we present DeepMAPS for biological network inference from scMulti-omics. It models scMulti-omics in a heterogeneous graph and learns relations among cells and genes within both local and global contexts in a robust manner using a multi-head graph transformer. Benchmarking results indicate DeepMAPS performs better than existing tools in cell clustering and biological network construction. It also showcases competitive capability in deriving cell-type-specific biological networks in lung tumor leukocyte CITE-seq data and matched diffuse small lymphocytic lymphoma scRNA-seq and scATAC-seq data. In addition, we deploy a DeepMAPS webserver equipped with multiple functionalities and visualizations to improve the usability and reproducibility of scMulti-omics data analysis. Single-cell multi-omics and deep learning could lead to the inference of biological networks across specific cell types. Here, the authors develop DeepMAPS, a deep learning, graph-based approach for cell-type specific network inference from single-cell multi-omics data that is tested on healthy and tumour tissue datasets.

The immune system is the hard-wired host defense mechanism against pathogens as well as cancer. Five years ago, we pondered the question if the era of cancer immunotherapy was upon us (Li et al., Exp Hem Oncol 2013). Exciting progresses have been made at all fronts since then, including (1) sweeping approval of six agents by the US Food and Drug Administration (FDA) to block the PD-1/PD-L1 pathway for treatment of 13 cancer types; (2) a paradigm shifting indication of PD-1 and CTLA4 blockers for the management of a broad class of cancers with DNA mismatch repair defect, the first-ever tissue agnostic approval of cancer drugs; (3) real world practice of adoptive T cell therapy with two CD19-directed chimeric antigen receptor T cell products (CAR-T) for relapsed and/or refractory B cell malignancies including acute lymphoid leukemia and diffuse large B cell lymphoma, signaling the birth of a field now known as synthetic immunology; (4) the award of 2018 Nobel Prize in Physiology and Medicine from the Nobel Committee to Tasuku Honjo and James Allison “for their discovery of cancer medicine by inhibition of negative immune regulation” ( www.nobelprize.org/prizes/medicine/2018 ); and (5) the emerging new concept of normalizing rather than amplifying anti-tumor immunity for guiding the next wave of revolution in the field of immuno-oncology (IO) (Sanmamed and Chen, Cell 2018). This article will highlight the significant developments of immune-oncology as of October 2018. The US FDA approved indications of all seven immune checkpoint blockers, and two CD19-directed CAR-T products are tabulated for easy references. We organized our discussion into the following sections: introduction, cell therapy, emerging immunotherapeutic strategies, expediting oncology drug development in an era of breakthrough therapies, new concepts in cancer immunology and immunotherapy, and concluding remarks. Many of these topics were covered by the 2018 China Cancer Immunotherapy Workshop in Beijing, the fourth annual conference co-organized by the Chinese American Hematologist and Oncologist Network (CAHON), China FDA (CFDA; now known as China National Medical Product Administration (NMPA)), and the Tsinghua University. We significantly expanded our discussion of important IO developments beyond what were covered in the conference, and proposed a new Three Rs conceptual framework for cancer immunotherapy, which is to reverse tolerance, rejuvenate the immune system, and restore immune homeostasis. We conclude that the future of immuno-oncology as a distinct discipline of cancer medicine has arrived.

Loss of the Y chromosome (LOY) is observed in multiple cancer types, including 10–40% of bladder cancers 1 – 6 , but its clinical and biological significance is unknown. Here, using genomic and transcriptomic studies, we report that LOY correlates with poor prognoses in patients with bladder cancer. We performed in-depth studies of naturally occurring LOY mutant bladder cancer cells as well as those with targeted deletion of Y chromosome by CRISPR–Cas9. Y-positive (Y + ) and Y-negative (Y – ) tumours grew similarly in vitro, whereas Y − tumours were more aggressive than Y + tumours in immune-competent hosts in a T cell-dependent manner. High-dimensional flow cytometric analyses demonstrated that Y − tumours promote striking dysfunction or exhaustion of CD8 + T cells in the tumour microenvironment. These findings were validated using single-nuclei RNA sequencing and spatial proteomic evaluation of human bladder cancers. Of note, compared with Y + tumours, Y − tumours exhibited an increased response to anti-PD-1 immune checkpoint blockade therapy in both mice and patients with cancer. Together, these results demonstrate that cancer cells with LOY mutations alter T cell function, promoting T cell exhaustion and sensitizing them to PD-1-targeted immunotherapy. This work provides insights into the basic biology of LOY mutation and potential biomarkers for improving cancer immunotherapy. Loss of the Y chromosome in tumour cells is associated with a poor prognosis for patients with bladder cancer by causing local T cell exhaustion, which also increases the response to immune checkpoint blockade therapy.

Immune checkpoint inhibitors targeting programmed cell death protein 1, programmed death-ligand 1, and cytotoxic T-lymphocyte-associated protein 4 provide deep and durable treatment responses which have revolutionized oncology. However, despite over 40% of cancer patients being eligible to receive immunotherapy, only 12% of patients gain benefit. A key to understanding what differentiates treatment response from non-response is better defining the role of the innate immune system in anti-tumor immunity and immune tolerance. Teleologically, myeloid cells, including macrophages, dendritic cells, monocytes, and neutrophils, initiate a response to invading pathogens and tissue repair after pathogen clearance is successfully accomplished. However, in the tumor microenvironment (TME), these innate cells are hijacked by the tumor cells and are imprinted to furthering tumor propagation and dissemination. Major advancements have been made in the field, especially related to the heterogeneity of myeloid cells and their function in the TME at the single cell level, a topic that has been highlighted by several recent international meetings including the 2021 China Cancer Immunotherapy workshop in Beijing. Here, we provide an up-to-date summary of the mechanisms by which major myeloid cells in the TME facilitate immunosuppression, enable tumor growth, foster tumor plasticity, and confer therapeutic resistance. We discuss ongoing strategies targeting the myeloid compartment in the preclinical and clinical settings which include: (1) altering myeloid cell composition within the TME; (2) functional blockade of immune-suppressive myeloid cells; (3) reprogramming myeloid cells to acquire pro-inflammatory properties; (4) modulating myeloid cells via cytokines; (5) myeloid cell therapies; and (6) emerging targets such as Siglec-15, TREM2, MARCO, LILRB2, and CLEVER-1. There is a significant promise that myeloid cell-based immunotherapy will help advance immuno-oncology in years to come.

Cancer immunotherapy has reached a critical point, now that immune checkpoint inhibitors and two CAR-T products have received market approval in treating 16 types of cancers and 1 tissue-agnostic cancer indication. Accompanying these advances, the 2018 Nobel Prize was awarded for the discovery of immune checkpoint pathways, which has led to the revolution of anti-cancer treatments. However, expanding the indications of immuno-oncology agents and overcoming treatment resistance face mounting challenges. Although combination immunotherapy is an obvious strategy to pursue, the fact that there have been more failures than successes in this effort has served as a wake-up call, placing emphasis on the importance of building a solid scientific foundation for the development of next-generation immuno-oncology (IO) agents. The 2019 China Cancer Immunotherapy Workshop was held to discuss the current challenges and opportunities in IO. At this conference, emerging concepts and strategies for IO development were proposed, focusing squarely on correcting the immunological defects in the tumor microenvironment. New targets such as Siglec-15 and new directions including neoantigens, cancer vaccines, oncolytic viruses, and cytokines were reviewed. Emerging immunotherapies were discussed in the areas of overcoming primary and secondary resistance to existing immune checkpoint inhibitors, activating effector cells, and targeting immunosuppressive mechanisms in the tumor microenvironment. In this article, we highlight old and new waves of IO therapy development, and provide perspectives on the latest momentum shifts in cancer immunotherapy.

The endoplasmic reticulum (ER) is an organelle equipped with mechanisms for proper protein folding, trafficking, and degradation to maintain protein homeostasis in the secretory pathway. As a defense mechanism, perturbation of ER proteostasis by ER stress agents activates a cascade of signaling pathways from the ER to the nucleus known as unfolded protein response (UPR). The primary goal of UPR is to induce transcriptional and translational programs to restore ER homeostasis for cell survival. As such, defects in UPR signaling have been implicated as a key contributor to multiple diseases including metabolic diseases, degenerative diseases, inflammatory disorders, and cancer. Growing evidence support the critical role of ER stress in regulating the fate as well as the magnitude of the immune response. Moreover, the availability of multiple UPR pharmacological inhibitors raises the hope that targeting UPR can be a new strategy for immune modulation and immunotherapy of diseases. This paper reviews the principal mechanisms by which ER stress affects immune cell biology and function, with a focus of discussion on UPR-associated immunopathology and the development of potential ER stress-targeted therapeutics.

Less than a year since the start of the COVID-19 pandemic, ten vaccines against SARS-CoV-2 have been approved for at least limited use, with over sixty others in clinical trials. This swift achievement has generated excitement and arrives at a time of great need, as the number of COVID-19 cases worldwide continues to rapidly increase. Two vaccines are currently approved for full use, both built on mRNA and lipid nanotechnology platforms, a success story of mRNA technology 20 years in the making. For patients with cancer, questions arise around the safety and efficacy of these vaccines in the setting of immune alterations engendered by their malignancy and/or therapies. We summarize the current data on leading COVID-19 vaccine candidates and vaccination of patients undergoing immunomodulatory cancer treatments. Most current cancer therapeutics should not prevent the generation of protective immunity. We call for more research in this area and recommend that the majority of patients with cancer receive COVID vaccinations when possible.

Rare cell populations are key in neoplastic progression and therapeutic response, offering potential intervention targets. However, their computational identification and analysis often lag behind major cell types. To fill this gap, we introduce MarsGT: Multi-omics Analysis for Rare population inference using a Single-cell Graph Transformer. It identifies rare cell populations using a probability-based heterogeneous graph transformer on single-cell multi-omics data. MarsGT outperforms existing tools in identifying rare cells across 550 simulated and four real human datasets. In mouse retina data, it reveals unique subpopulations of rare bipolar cells and a Müller glia cell subpopulation. In human lymph node data, MarsGT detects an intermediate B cell population potentially acting as lymphoma precursors. In human melanoma data, it identifies a rare MAIT-like population impacted by a high IFN-I response and reveals the mechanism of immunotherapy. Hence, MarsGT offers biological insights and suggests potential strategies for early detection and therapeutic intervention of disease. Identifying rare cell populations is key to understanding cancer progression and response to therapy. Here, authors introduce MarsGT, an end-to-end deep learning model for rare cell population identification from scMulti-omics data.