Checkpoint blockade immunotherapies can be extraordinarily effective, but might benefit only the minority of patients whose tumors are pre-infiltrated by T cells. Here, using lung adenocarcinoma ...mouse models, including genetic models, we show that autochthonous tumors that lacked T cell infiltration and resisted current treatment options could be successfully sensitized to host antitumor T cell immunity when appropriately selected immunogenic drugs (e.g., oxaliplatin combined with cyclophosphamide for treatment against tumors expressing oncogenic Kras and lacking Trp53) were used. The antitumor response was triggered by direct drug actions on tumor cells, relied on innate immune sensing through toll-like receptor 4 signaling, and ultimately depended on CD8+ T cell antitumor immunity. Furthermore, instigating tumor infiltration by T cells sensitized tumors to checkpoint inhibition and controlled cancer durably. These findings indicate that the proportion of cancers responding to checkpoint therapy can be feasibly and substantially expanded by combining checkpoint blockade with immunogenic drugs.
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•Kras/Trp53 mutant tumors lack CD8+ T cells and resist chemo- and immunotherapies•Immunogenic chemotherapy elicits tumor T cell infiltration and controls cancer growth•Tumor control requires CD8+ T cells, TLR4+ cells, and drug actions on cancer cells•T cell influx sensitizes tumors to checkpoint inhibition and durably controls cancer
There is an urgent need to expand the proportion of patients that respond to immune checkpoint therapy. Using clinically relevant genetic mouse models and a combination of immunogenic drugs to trigger T cell infiltration into tumors, Pittet and colleagues are able to make unresponsive tumors sensitive to checkpoint blockade therapy.
Twenty years ago, R. Steinman and colleagues established that dendritic cells (DCs) have unique capacities to prime naive T cells and that DC maturation is the checkpoint for the initiation of ...adaptive immune responses. In the mid-1990s, C. Janeway pointed out the pivotal role of innate effectors in dictating adaptive immune responses while few researchers wondered why antigens were much more immunogenic for the specific immune system when applied with "adjuvants" that stimulated innate immunity. DC "maturation" appears to be the cornerstone between innate and cognate immunity, but what regulates DC maturation? DCs are sensors of infection and danger and pathways leading to DC activation involve at least toll like receptors and/or proinflammatory cytokine and chemokine receptors. However, in non-microbial scenarios such as tumorigenesis, transplantation, or atopy, DC activation might be regulated through other mechanisms whereby a third party cell could convey stress signals to DCs. The activated NK cell could be this third party cell, capable of directly triggering DC maturation. In this issue of The Journal of Experimental Medicine, three articles shed some light on the regulatory role of NK cells on the control of DC functions. The relevance of innate effectors such as NK cells in resistance to herpes viridae-related infections and tumors is being established. NK cell effector functions are regulated by the balance of activating and inhibitory signals transmitted by membrane receptors that recognize ligands on the cell surface of potential target cells. But which mechanisms contribute to the "priming" phase of NK cell activation? While so far, experimental model systems exploring NK cell recognition patterns used IL-2, a lymphokine downstream of T cell activation, there is a role for NK cells early on, before cognate T cell activation for the control of MCMV viral infections. It was proposed by Fernandez et al. in a mouse model that DCs could act on the priming arm of innate immunity by triggering NK cell effector functions in vitro and in vivo in the setting of a tumor. In line with this observation, bone marrow-derived DCs were shown to be pivotal for the control of hepatic mouse NKT cell activation. In this issue of The Journal of Experimental Medicine, three articles analyze the regulation of NK cell functions by DCs in human in vitro model systems demonstrating that DCs can act on the priming phase of NK cell activation. This commentary tries to highlight a few important links between the two players of innate immunity, DCs and NK cells, which may impinge on the course of immune disorders or translate into novel avenues for therapy.
Natural killer (NK) cells were originally defined as effector lymphocytes of innate immunity endowed with constitutive cytolytic functions. More recently, a more nuanced view of NK cells has emerged. ...NK cells are now recognized to express a repertoire of activating and inhibitory receptors that is calibrated to ensure self-tolerance while allowing efficacy against assaults such as viral infection and tumor development. Moreover, NK cells do not react in an invariant manner but rather adapt to their environment. Finally, recent studies have unveiled that NK cells can also mount a form of antigen-specific immunologie memory. NK cells thus exert sophisticated biological functions that are attributes of both innate and adaptive immunity, blurring the functional borders between these two arms of the immune response.
The composition of the gut microbiome has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment, but there is limited consensus on the specific microbiome ...characteristics linked to the clinical benefits of ICIs. We performed shotgun metagenomic sequencing of stool samples collected before ICI initiation from five observational cohorts recruiting ICI-naive patients with advanced cutaneous melanoma (n = 165). Integrating the dataset with 147 metagenomic samples from previously published studies, we found that the gut microbiome has a relevant, but cohort-dependent, association with the response to ICIs. A machine learning analysis confirmed the link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs but also revealed limited reproducibility of microbiome-based signatures across cohorts. Accordingly, a panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila, associated with responders was identified, but no single species could be regarded as a fully consistent biomarker across studies. Overall, the role of the human gut microbiome in ICI response appears more complex than previously thought, extending beyond differing microbial species simply present or absent in responders and nonresponders. Future studies should adopt larger sample sizes and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course.
In response to some chemotherapeutic agents such as anthracyclines and oxaliplatin, cancer cells undergo immunogenic apoptosis, meaning that their corpses are engulfed by dendritic cells and that ...tumor cell antigens are presented to tumor-specific CD8(+) T cells, which then control residual tumor cells. One of the peculiarities of immunogenic apoptosis is the early cell surface exposure of calreticulin (CRT), a protein that usually resides in the lumen of the endoplasmic reticulum (ER). When elicited by anthracyclines or oxaliplatin, the CRT exposure pathway is activated by pre-apoptotic ER stress and the phosphorylation of the eukaryotic translation initiation factor eIF2alpha by the kinase PERK, followed by caspase-8-mediated proteolysis of the ER-sessile protein BAP31, activation of the pro-apoptotic proteins Bax and Bak, anterograde transport of CRT from the ER to the Golgi apparatus and exocytosis of CRT-containing vesicles, finally resulting in CRT translocation onto the plasma membrane surface. Interruption of this complex pathway abolishes CRT exposure, annihilates the immunogenicity of apoptosis, and reduces the immune response elicited by anticancer chemotherapies. We speculate that human cancers that are incapable of activating the CRT exposure pathway are refractory to the immune-mediated component of anticancer therapies.
Toll-like receptor (TLR) agonists demonstrate therapeutic promise as immunological adjuvants for anticancer immunotherapy. To date, three TLR agonists have been approved by US regulatory agencies for ...use in cancer patients. Additionally, the potential of hitherto experimental TLR ligands to mediate clinically useful immunostimulatory effects has been extensively investigated over the past few years. Here, we summarize recent preclinical and clinical advances in the development of TLR agonists for cancer therapy.
Toll-like receptor 3 (TLR3) is a pattern recognition receptor that senses exogenous (viral) as well as endogenous (mammalian) double-stranded RNA in endosomes. On activation, TLR3 initiates a signal ...transduction pathway that culminates with the secretion of pro-inflammatory cytokines including type I interferon (IFN). The latter is essential not only for innate immune responses to infection but also for the initiation of antigen-specific immunity against viruses and malignant cells. These aspects of TLR3 biology have supported the development of various agonists for use as stand-alone agents or combined with other therapeutic modalities in cancer patients. Here, we review recent preclinical and clinical advances in the development of TLR3 agonists for oncological disorders.
cDC, conventional dendritic cell; CMT, cytokine modulating treatment; CRC, colorectal carcinoma; CTL, cytotoxic T lymphocyte; DC, dendritic cell; dsRNA, double-stranded RNA; FLT3LG, fms-related receptor tyrosine kinase 3 ligand; HNSCC, head and neck squamous cell carcinoma; IFN, interferon; IL, interleukin; ISV, in situ vaccine; MUC1, mucin 1, cell surface associated; PD-1, programmed cell death 1; PD-L1, programmed death-ligand 1; polyA:U, polyadenylic:polyuridylic acid; polyI:C, polyriboinosinic:polyribocytidylic acid; TLR, Toll-like receptor
The term 'immunogenic cell death' (ICD) denotes an immunologically unique type of regulated cell death that enables, rather than suppresses, T cell-driven immune responses that are specific for ...antigens derived from the dying cells. The ability of ICD to elicit adaptive immunity heavily relies on the immunogenicity of dying cells, implying that such cells must encode and present antigens not covered by central tolerance (antigenicity), and deliver immunostimulatory molecules such as damage-associated molecular patterns and cytokines (adjuvanticity). Moreover, the host immune system must be equipped to detect the antigenicity and adjuvanticity of dying cells. As cancer (but not normal) cells express several antigens not covered by central tolerance, they can be driven into ICD by some therapeutic agents, including (but not limited to) chemotherapeutics of the anthracycline family, oxaliplatin and bortezomib, as well as radiation therapy. In this Trial Watch, we describe current trends in the preclinical and clinical development of ICD-eliciting chemotherapy as partner for immunotherapy, with a focus on trials assessing efficacy in the context of immunomonitoring.
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