Cancer immunology and immunotherapy

Cancer immunology research is diverse, uses cutting-edge technologies and continues to excite with its constantly evolving contribution to new therapeutic options, and not just for patients with cancer.

This Review on the interplay between the immune system and metastasis is part of our wider Series of Reviews on Cancer Immunology and Immunotherapy.

In this Review, the authors analyze functional and dysfunctional T cell features to make sense of cancer immunotherapy efficacy and how to improve it.

In this Review, the authors summarize the literature around immune cancer cell STING signaling and how it is finely balanced between pro-tumorigenic and anti-tumorigenic functions.

We are in the midst of an explosion of multiomics and spatial data along with constant innovation of the tools used to study these data. In this Review article, as part of our Cancer Immunology and Immunotherapy series, the authors discuss these innovations and their application to study the tumor microenvironment.

Here the authors review CAR T cell engineering and immunotherapy for cancer and juxtapose state-of-the-art developments with CAR NK cells as part of our Cancer Immunology series of Reviews.

Bantug and Hess discuss the metabolic interplay between tumor-resident cells and how the effect of metabolism-targeted anticancer strategies on non-transformed or immune cells in the tumor needs to be considered.

Malmberg and colleagues generated a single-cell transcriptional reference map to investigate pan-cancer profiles of tumor-infiltrating natural killer cells.

Here the authors show that BTLA on effector T cells interacts with HVEM on other immunosuppressive cells in the tumor microenvironment. The authors also present evidence that overcoming this checkpoint can ehance CAR T functionality.

Chronic antigen exposure promotes terminal exhaustion of T cells. Here the authors show a role for TCR stimulation in preserving progenitor exhausted T cells and highlight their TCR-dependent self-renewal during antitumor responses.

Cancer and aging are associated with each other, but underlying mechanisms contributing to this correlation are unclear. Here the authors identify a dysfunctional T cell state that is distinct from typical T cell exhaustion and only occurs in the tumor microenvironment during later life.

In this Resource paper, the authors integrate T cell antigen receptor, B cell antigen receptor and exome sequencing comparing early and metastatic breast cancer in humans, showing how the immune response and tumors coevolve.

Here the authors show that a heteropolysaccharide from a commensal bacteria commonly found in the Korean food kimchi is able to bolster antitumor immune responses by instructing tumor-associated macrophages to release lipocalin-2, which sequesters iron away from tumor cells contributing to the immune response to attack these cells.

Here the authors show how the liver affects the immune response to pancreatic ductal adenocarcinoma and that cancer immunity and survival outcomes after surgery might be bolstered by therapeutic intervention on hepatocyte release of serum amyloid A proteins.

Cupedo and colleagues show that neutrophils promote a tumor-supportive microenvironment via a self-amplifying interaction between neutrophils and bone marrow stromal cells. This scenario creates a promyeloma niche that is difficult to treat despite targeted therapies directed at the myeloma cells.

CD103⁺ T cells are associated with control over tumors but how this is mediated is unclear. Here the authors show that CD61 colocalizes and functionally combines with CD103 in the T cell synaptic response to promote antitumor T cell responses.

The spatial organization of cells in solid tumors is considered to be important for immune response and response to therapy. Here the authors use multiomics including spatial transcriptomics of human lung tumors prior to patients being treated and show among other things an association of stem-immunity hubs rich in stem-like CD8⁺ T cells with positive response to anti-PD-1 therapy.

Here the authors present a method they call CM-Drug for the identification of combination drugs that can boost the efficacy of immune checkpoint blockade therapy. They validate this method with melanoma and lung cancer models in mice and explore in further depth one hit from their screen, the thyrotropin-releasing hormone (TRH) analog taltirelin.

Here, the authors target intratumoral T_reg cells to enhance antitumor immunity without affecting systemic T_reg cell function and identify JMJD1C as a critical epigenetic regulator of tumor T_reg cell fitness.

IL-23 promotes tumor growth in preclinical cancer models and correlates with adverse clinical outcomes. Here, Becher and colleagues find that IL-23 produced by tumor-associated macrophages stabilizes T_reg cell identity, promoting immunosuppression and tumor growth.

Here the authors show that lithium carbonate can revitalize tumor-reactive CD8⁺T cells by shunting cytosolic lactic acid into the mitochondria for oxidation, indicating that lithium ions might be applied as a cancer immunotherapy.

Here the authors show that immune cell exclusion and immunosuppression in the melanoma microenviromment are driven by nerve growth factor interactions with tropomyosin receptor kinase A on melanoma cells and that a tropomyosin receptor kinase inhibitor can sensitize these tumors to immune checkpoint blockade.

Carnosine is a mobile buffering metabolite. Here the authors link carnosine accumulation, hypoxia and intracellular pH homeostasis in cancer cells as a mechanism of tumor immune evasion via NFX1 degradation and galectin-9 activity.

Induced pluripotent stem cell (iPSC)-derived macrophages (iMACs) are being used to make chimeric antigen receptor (CAR) macrophages for immunotherapy. Here the authors design a second-generation macrophage-specific CAR by integrating CD3ζ and toll/IL-1R (TIR) domains resulting in an M1-polarized CAR-iMAC with increased antitumor functions.

Veillette and colleagues show that CD47 on tumor cells interacts in cis with the pro-phagocytic ligand SLAMF7, masking the ability of SLAMF7 to engage its homotypic receptor on macrophages and to trigger phagocytosis.

Minguet and colleagues systematically examine how individual CD3 chains of the TCR–CD3 complex can improve chimeric antigen receptor (CAR) T cell performance.

Yuan and colleagues show that ERMAP expression on cancer cells delivers an ‘eat me’ signal to Kupffer cells by binding to Gal-9–dectin-2 on Kupffer cells and triggering phagocytosis.

Here, the authors show that deletion of Pglyrp1 promotes antitumor immunity owing to its inhibitory function in CD8⁺ T cells and that targeting it can inhibit development of autoimmune neuroinflammation. These findings indicate that PGLYRP1 might be a target for immunotherapy.

Verdeil and colleagues show that the transcription factor NFAT5 is selectively required in tumor-induced, but not chronic infection-induced, CD8⁺ T cell exhaustion, possibly due to the modulation of NFAT5 activation by hyperosmolarity in the tumor environment.

Here the authors show that TFPI2 promotes glioblastoma stem cell self-renewal and connects stemness to microglia immunosuppression, plus targeting TFPI2-mediated glioblastoma stem cell–microglia symbiosis inhibits tumor growth and synergizes with anti-PD1 therapy in glioblastoma.

Single-cell and spatial analyses of conserved regulatory T (T_reg) cell-dependent transcriptional states of diverse accessory cell types in mouse and human lung cancer suggest rational T_reg cell targeting-based combination therapy for PD-1 blockade-resistant tumors.

NK cells require an immunological synapse to kill cancer cells and these synapses have been shown to have membranous protrusions. Here the authors use cutting-edge imaging and other techniques to show that tumor serine metabolism results in a reduction in NK cell sphingomyelin content and a lack of these membranous protrusions, which could contribute to a failure to kill cancer cells.

γδ T cells contribute to cancer immunity by killing tumor cells, but their function in the context of immune checkpoint inhibition is less clear. Here the authors show that a Vδ2⁻ subset of γδ T cells in human kidney tumors phenotypically resembles exhausted T cells yet retains this cytolytic function and can be used to predict response to immune checkpoint inhibition.

Here, the authors show that CD8⁺ T cells egress from tumors via lymphatic vessels in a CXCL12/CXCR4-dependent manner. High-affinity antigen encounter inhibits CXCR4 and increases retention, while no encounter or weak affinity directs T cell exit to limit local tumor control.

Unlike metabolic reprogramming that is characteristic of macrophage inflammatory polarization responses to lipopolysaccharide and TLR4 stimulation, the metabolism underlying inflammatory responses to CD40 signaling is not well characterized. Here the authors show CD40 signaling drives fatty acid oxidation and glutamine metabolism resulting in regulation of the NAD⁺/NADH ratio, which in turn promotes antitumor and pro-inflammatory macrophage functions.

Ha and colleagues show that loss of PD-1 expression on regulatory T cells in the tumor environment reduces their metabolic fitness and proliferative capacity.

Cancer immunotherapies can be limited by terminally dysfunctional T cells in the tumor microenvironment. Here the authors present a model of stable human T cell dysfunction to show that TGFβ contributes to this terminal dysfunction which can be therapeutically inhibited by simultaneously blocking TGFβ1 and boosting bone morphogenetic protein (BMP) signaling.

Exhausted CD8⁺ T cells with diminished effector functions accumulate in tumors. Here, the authors show that hypoxia induces a suppressive phenotype in exhausted T cells and that interfering with hypoxia-mediated CD39 expression limits immunosuppression in the tumor and augments immunotherapy, resulting in arrest of tumor growth.

Modeling a rare bone marrow failure disorder due to haploinsufficiency for the MECOM transcription factor identifies a human hematopoietic stem cell regulatory network, which is co-opted by high-risk leukemias.

Type I interferons have been described to have protumor or antitumor functions depending on context. Here the authors show a protumor function for type I interferons in that they promote cancer stem cells by upregulating the chromatin remodeling factor KDM1B.

Chronic antigen stimulation leads to CD8⁺ T cell exhaustion, which is mediated by persistent activation of the transcription factor NFAT in the absence of AP-1. Seo, González-Avalos and colleagues show that overexpressed BATF cooperates with IRF4 to counteract NFAT-induced exhaustion and promote better tumor control by CAR T cells in mouse models.

Predicting which patients will respond to checkpoint blocking therapies is a major challenge. Here the authors score the epigenetic imprinting of T cell responsiveness to type 1 interferons and use this information to predict response to anti-PD1 therapy and long-term survival of cancer patients.

How the immune system responds to epithelial cancers beyond neoantigen-driven adaptive immunity is poorly understood. Kansler et al. reveal an innate immune surveillance response mediated by cytotoxic ILC1 sensing of cancer cell-expressed IL-15.

Single-cell RNAseq during initiation and progression of mouse glioblastoma reveals a dynamic immune microenvironment transitioning from pro-inflammatory microglia in early tumors towards an infiltrating macrophage and suppressor cell-centric immune landscape in late-stage tumors.

Group 2 innate lymphoid cells (ILC2s) are generally considered to have pro-tumor functions. However, Belz and colleagues demonstrate that ILC2s have anti-melanoma effects due to their high production of the inflammatory cytokine granulocyte-macrophage colony-stimulating factor in the tumor microenvironment.

Tang and colleagues show that a half-life-extended IL-10–Fc fusion protein acts directly on terminally exhausted PD1⁺TIM-3⁺CD8⁺ T cells to enhance their proliferation and effector function by reprogramming the cellular metabolism to oxidative phosphorylation in a mitochondrial pyruvate carrier–dependent manner. Treatment of tumor-bearing mice with IL-10–Fc and adoptive T cell therapy led to eradication of their established solid tumors and durable cures.

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.