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Immune checkpoint inhibitors (ICIs) reinvigorate anti-tumor immune responses by disrupting co-inhibitory immune checkpoint molecules such as programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4). Although ICIs have had unprecedented success and have become the standard of care for many cancers, they are often accompanied by off-target inflammation that can occur in any organ system. These immune related adverse events (irAEs) often require steroid use and/or cessation of ICI therapy, which can both lead to cancer progression. Although irAEs are common, the detailed molecular and immune mechanisms underlying their development are still elusive. To further our understanding of irAEs and develop effective treatment options, there is pressing need for preclinical models recapitulating the clinical settings. In this review, we describe current preclinical models and immune implications of ICI-induced skin toxicities, colitis, neurological and endocrine toxicities, pneumonitis, arthritis, and myocarditis along with their management. [ABSTRACT FROM AUTHOR]

The deadliest anaplastic thyroid cancer (ATC) often transforms from indolent differentiated thyroid cancer (DTC); however, the complex intratumor transformation process is poorly understood. We investigated an anaplastic transformation model by dissecting both cell lineage and cell fate transitions using single-cell transcriptomic and genetic alteration data from patients with different subtypes of thyroid cancer. The resulting spectrum of ATC transformation included stress-responsive DTC cells, inflammatory ATC cells (iATCs), and mitotic-defective ATC cells and extended all the way to mesenchymal ATC cells (mATCs). Furthermore, our analysis identified 2 important milestones: (a) a diploid stage, in which iATC cells were diploids with inflammatory phenotypes and (b) an aneuploid stage, in which mATCs gained aneuploid genomes and mesenchymal phenotypes, producing excessive amounts of collagen and collagen-interacting receptors. In parallel, cancer- associated fibroblasts showed strong interactions among mesenchymal cell types, macrophages shifted from M1 to M2 states, and T cells reprogrammed from cytotoxic to exhausted states, highlighting new therapeutic opportunities for the treatment of ATC., Introduction Anaplastic thyroid cancer (ATC), characterized by an undifferentiated morphology, is arguably one of the most lethal malignancies. According to Surveillance, Epidemiology and End Results (SEER) data (released April 2021) [...]

Immune evasion is an emerging hallmark of cancer progression. However, functional studies to understand the role of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment are limited by the lack of available specific cell surface markers. We adapted a competitive peptide phage display platform to identify candidate peptides binding MDSCs specifically and generated peptide-Fc fusion proteins (peptibodies). In multiple tumor models, intravenous peptibody injection completely depleted blood, splenic and intratumoral MDSCs in tumor-bearing mice without affecting proinflammatory immune cell types, such as dendritic cells. Whereas control Gr-1-specific antibody primarily depleted granulocytic MDSCs, peptibodies depleted both granulocytic and monocytic MDSC subsets. Peptibody treatment was associated with inhibition of tumor growth in vivo, which was superior to that achieved with Gr-1-specific antibody. Immunoprecipitation of MDSC membrane proteins identified S100 family proteins as candidate targets. Our strategy may be useful to identify new diagnostic and therapeutic surface targets on rare cell subtypes, including human MDSCs., Activating the immune system has emerged as a promising way to treat cancer. Recent successful phase 3 clinical trials of therapeutic cancer vaccines include the US Food and Drug Administration-approved [...]

In immune responses, activated T cells migrate to B-cell follicles and develop into follicular T-helper ([T.sub.FH]) cells, a recently identified subset of [CD4.sup.+] T cells specialized in providing help to B lymphocytes in the induction of germinal centres (1,2). Although Bcl6 has been shown to be essential in [T.sub.FH]-cell function, it may not regulate the initial migration of T cells (3) or the induction of the [T.sub.FH] program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation (4). Here we show that expression of achaete-scute homologue 2 (Ascl2)--a basic helix-loop-helix (bHLH) transcription factor (5)--is selectively upregulated in [T.sub.FH] cells. Ectopic expression of Ascl2 upregulates CXCR5 but not Bcl6, and downregulates C-C chemokine receptor 7 (CCR7) expression in T cells in vitro, as well as accelerating T-cell migration to the follicles and [T.sub.FH]-cell development in vivo in mice. Genome-wide analysis indicates that Ascl2 directly regulates [T.sub.FH]-related genes whereas it inhibits expression of T-helper cell 1 ([T.sub.H]1) and [T.sub.H]17 signature genes. Acute deletion of Ascl2, as well as blockade of its function with the Id3 protein in [CD4.sup.+] T cells, results in impaired [T.sub.FH]-cell development and germinal centre response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances [T.sub.FH]-cell generation. Thus, Ascl2 directly initiates [T.sub.FH]-cell development., The development of [T.sub.FH] cells is initiated by and dependent on their movement out of the T-cell zone and into the B-cell follicle. This migration process is regulated by upregulation [...]

[Foxp3.sup.+] regulatory T ([T.sub.reg]) cells suppress different types of immune responses to help maintain homeostasis in the body. How [T.sub.reg] cells regulate humoral immunity, including germinal center reactions, is unclear. Here we identify a subset of [T.sub.reg] cells expressing CXCR5 and Bcl-6 that localize to the germinal centers in mice and humans. The expression of CXCR5 on [T.sub.reg] cells depends on Bcl-6. These [CXCR5.sup.+][Bcl-6.sup.+] [T.sub.reg] cells are absent in the thymus but can be generated de novo from CXCR5-[Foxp3.sup.+] natural [T.sub.reg] precursors. A lack of CXCR5+ [T.sub.reg] cells leads to greater germinal center reactions including germinal center B cells, affinity maturation of antibodies and the differentiation of plasma cells. These results unveil a Bcl-6-CXCR5 axis in [T.sub.reg] cells that drives the development of follicular regulatory T ([T.sub.FR]) cells that function to inhibit the germinal center reactions., The vertebrate immune system contains a unique subset of T cells expressing Foxp3 that prevent autoimmunity against self antigens and exaggerated immune responses. Deficiency of Foxp3 in humans results in [...]

T-cell tolerance is a major obstacle to successful cancer immunotherapy; thus, developing strategies to break immune tolerance is a high priority. Here we show that expression of the E3 ubiquitin ligase Grail is upregulated in CD8+ T cells that have infiltrated into transplanted lymphoma tumours, and Grail deficiency confers long-term tumour control. Importantly, therapeutic transfer of Grail-deficient CD8+ T cells is sufficient to repress established tumours. Mechanistically, loss of Grail enhances anti-tumour reactivity and functionality of CD8+ T cells. In addition, Grail-deficient CD8+ T cells have increased IL-21 receptor (IL-21R) expression and hyperresponsiveness to IL-21 signalling as Grail promotes IL-21R ubiquitination and degradation. Moreover, CD8+ T cells isolated from lymphoma patients express higher levels of Grail and lower levels of IL-21R, compared with CD8+ T cells from normal donors. Our data demonstrate that Grail is a crucial factor controlling CD8+ T-cell function and is a potential target to improve cytotoxic T-cell activity. [ABSTRACT FROM AUTHOR]