Explore the vast range of titles available.

In 1986, Mosmann and Coffman identified 2 functionally distinct subsets of activated CD4 T cells, Th1 and Th2 cells, being key in distinct T cell mediated responses. Over the past three decades, our understanding of CD4 T cell differentiation has expanded and the initial paradigm of a dichotomic CD4 T cell family has been revisited to accommodate a constantly growing number of functionally distinct CD4 T helper and regulatory subpopulations. Of note, CD4 T cells with cytotoxic functions have also been described, initially in viral infections, autoimmune disorders and more recently also in cancer settings. Here, we provide an historical overview on the discovery and characterization of cytotoxic CD4 T cells, followed by a description of their mechanisms of cytotoxicity. We emphasize the relevance of these cells in disease conditions, particularly in cancer, and we provide insights on how to exploit these cells in immunotherapy.

Predictions of epitopes presented by class II human leukocyte antigen molecules (HLA-II) have limited accuracy, restricting vaccine and therapy design. Here we combined unbiased mass spectrometry with a motif deconvolution algorithm to profile and analyze a total of 99,265 unique peptides eluted from HLA-II molecules. We then trained an epitope prediction algorithm with these data and improved prediction of pathogen and tumor-associated class II neoepitopes.

Depleting regulatory T cells (T reg cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral T reg cells is direly needed for cancer immunotherapy. We found that CD36 was selectively upregulated in intrautumoral T reg cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via peroxisome proliferator-activated receptor-β signaling, programming T reg cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in T reg cells suppressed tumor growth accompanied by a decrease in intratumoral T reg cells and enhancement of antitumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive antitumor responses with anti-programmed cell death protein 1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrates the survival and functions of intratumoral T reg cells, and the therapeutic potential of targeting this pathway for reprogramming the TME. Tumor environments are highly acidic due to high concentrations of lactic acid. Ho and colleagues report that tumor-infiltrating regulatory T cells adapt to this tumor environment by upregulating expression of CD36, which allows them to use fatty acids to fuel their metabolism.

The metabolic challenges present in tumors attenuate the metabolic fitness and antitumor activity of tumor-infiltrating T lymphocytes (TILs). However, it remains unclear whether persistent metabolic insufficiency can imprint permanent T cell dysfunction. We found that TILs accumulated depolarized mitochondria as a result of decreased mitophagy activity and displayed functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells. Mechanistically, reduced mitochondrial fitness in TILs was induced by the coordination of T cell receptor stimulation, microenvironmental stressors and PD-1 signaling. Enforced accumulation of depolarized mitochondria with pharmacological inhibitors induced epigenetic reprogramming toward terminal exhaustion, indicating that mitochondrial deregulation caused T cell exhaustion. Furthermore, supplementation with nicotinamide riboside enhanced T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal insights into how mitochondrial dynamics and quality orchestrate T cell antitumor responses and commitment to the exhaustion program. Ho and colleagues report that mitochondrial dysfunction and impaired mitophagy triggered by the tumor microenvironment lead to subsequent epigenetic changes and cause permanent T cell exhaustion and dysfunction.

Group 2 innate lymphoid cells (ILC2s) play a critical role in protection against helminths and in diverse inflammatory diseases by responding to soluble factors such as the alarmin IL-33, that is often overexpressed in cancer. Nonetheless, regulatory factors that dictate ILC2 functions remain poorly studied. Here, we show that peroxisome proliferator-activated receptor gamma (PPARγ) is selectively expressed in ILC2s in humans and in mice, acting as a central functional regulator. Pharmacologic inhibition or genetic deletion of PPARγ in ILC2s significantly impair IL-33-induced Type-2 cytokine production and mitochondrial fitness. Further, PPARγ blockade in ILC2s disrupts their pro-tumoral effect induced by IL-33-secreting cancer cells. Lastly, genetic ablation of PPARγ in ILC2s significantly suppresses tumor growth in vivo. Our findings highlight a crucial role for PPARγ in supporting the IL-33 dependent pro-tumorigenic role of ILC2s and suggest that PPARγ can be considered as a druggable pathway in ILC2s to inhibit their effector functions. Hence, PPARγ targeting might be exploited in cancer immunotherapy and in other ILC2-driven mediated disorders, such as asthma and allergy. Group 2 innate lymphoid cells (ILC2s) are a component of type 2 immune response recently described to be involved in the regulation of anti-tumor immune responses. Here, the authors show that the expression of the peroxisome proliferator-activated receptor γ (PPAPγ) in human and mouse ILC2 sustains type-2 cytokines secretion and support their pro-tumorigenic role in preclinical cancer models.

Assay for Transposase-Accessible Chromatin sequencing (ATAC-Seq) is a widely used technique to explore gene regulatory mechanisms. For most ATAC-Seq data from healthy and diseased tissues such as tumors, chromatin accessibility measurement represents a mixed signal from multiple cell types. In this work, we derive reliable chromatin accessibility marker peaks and reference profiles for most non-malignant cell types frequently observed in the microenvironment of human tumors. We then integrate these data into the EPIC deconvolution framework (Racle et al., 2017) to quantify cell-type heterogeneity in bulk ATAC-Seq data. Our EPIC-ATAC tool accurately predicts non-malignant and malignant cell fractions in tumor samples. When applied to a human breast cancer cohort, EPIC-ATAC accurately infers the immune contexture of the main breast cancer subtypes.

Alteration of the surface glycosylation pattern on malignant cells potentially affects tumor immunity by directly influencing interactions with glycan-binding proteins (lectins) on the surface of immunomodulatory cells. The sialic acid-binding Ig-like lectins Siglec-7 and -9 are MHC class I-independent inhibitory receptors on human NK cells that recognize sialic acid-containing carbohydrates. Here, we found that the presence of Siglec-9 defined a subset of cytotoxic NK cells with a mature phenotype and enhanced chemotactic potential. Interestingly, this Siglec-9+ NK cell population was reduced in the peripheral blood of cancer patients. Broad analysis of primary tumor samples revealed that ligands of Siglec-7 and -9 were expressed on human cancer cells of different histological types. Expression of Siglec-7 and -9 ligands was associated with susceptibility of NK cell-sensitive tumor cells and, unexpectedly, of presumably NK cell-resistant tumor cells to NK cell-mediated cytotoxicity. Together, these observations have direct implications for NK cell-based therapies and highlight the requirement to consider both MHC class I haplotype and tumor-specific glycosylation.

Innate lymphoid cells (ILCs) represent the most recently identified family of innate lymphocytes that act as first responders, maintaining tissue homeostasis and protecting epithelial barriers. In the last few years, group 2 ILCs (ILC2s) have emerged as key regulators in several immunological processes such as asthma and allergy. Whilst ILC2s are currently being evaluated as novel targets for immunotherapy in these diseases, their involvement in tumor immunity has only recently begun to be deciphered. Here, we provide a comprehensive overview of the pleiotropic roles of ILC2s in different tumor settings. Furthermore, we discuss how different therapeutic approaches targeting ILC2s could improve the efficacy of current tumor immunotherapies.

Group 2 innate lymphoid cells (ILC2s) are involved in human diseases, such as allergy, atopic dermatitis and nasal polyposis, but their function in human cancer remains unclear. Here we show that, in acute promyelocytic leukaemia (APL), ILC2s are increased and hyper-activated through the interaction of CRTH2 and NKp30 with elevated tumour-derived PGD2 and B7H6, respectively. ILC2s, in turn, activate monocytic myeloid-derived suppressor cells (M-MDSCs) via IL-13 secretion. Upon treating APL with all-trans retinoic acid and achieving complete remission, the levels of PGD2, NKp30, ILC2s, IL-13 and M-MDSCs are restored. Similarly, disruption of this tumour immunosuppressive axis by specifically blocking PGD2, IL-13 and NKp30 partially restores ILC2 and M-MDSC levels and results in increased survival. Thus, using APL as a model, we uncover a tolerogenic pathway that may represent a relevant immunosuppressive, therapeutic targetable, mechanism operating in various human tumour types, as supported by our observations in prostate cancer. Group 2 innate lymphoid cells (ILC2s) modulate inflammatory and allergic responses, but their function in cancer immunity is still unclear. Here the authors show that, in acute promyelocytic leukaemia, tumour-activated ILC2s secrete IL-13 to induce myeloid-derived suppressor cells and support tumour growth.