Mathematical model for immune checkpoint inhibitors with delayed responses

The induction of proinflammatory T cells by dendritic cell (DC) subtypes is critical for antitumor responses and effective immune checkpoint blockade (ICB) therapy. Here, we show that human CD1c+CD5+ DCs are reduced in melanoma-affected lymph nodes, with CD5 expression on DCs correlating with patient survival. Activating CD5 on DCs enhanced T cell priming and improved survival after ICB therapy. CD5+ DC numbers increased during ICB therapy, and low interleukin-6 (IL-6) concentrations promoted their de novo differentiation. Mechanistically, CD5 expression by DCs was required to generate optimally protective CD5hi T helper and CD8+ T cells; further, deletion of CD5 from T cells dampened tumor elimination in response to ICB therapy in vivo. Thus, CD5+ DCs are an essential component of optimal ICB therapy.

INTRODUCTION: CD73 catalyzes the extracellular generation of adenosine (ADO) from adenosine monophosphate (AMP). ADO suppresses immune responses, including those of T cells, NK cells and dendritic cells through activation of A2aR and A2bR receptors. Exhausted T cells and NK cells express high levels of several immune checkpoint proteins, including PD-1 and TIGIT. We present here preclinical data on the ability of CD73i to reverse effector cell suppression from exposure to ADO even in the presence of ICI. METHODS: CD73i effects in a monotherapeutic setting were assessed by CD3/CD28/CD2 T cell stimulation and cytolytic assays. Combinatorial settings were assessed using mixed lymphocyte reactions (MLRs). In vivo effects of CD73i + ICI were determined using syngeneic tumor models. RESULTS: CD73 is expressed across a wide range of tumor types, including those with limited response to anti-PD-1 therapy. CD73i completely rescued AMP-mediated inhibition of T cell proliferation and effector function as well as NK cell cytolytic function. AMP abrogated the enhanced allogeneic CD4+ T cell activation and IFN-γ production mediated by blocking PD-1/PD-L1 and TIGIT, an effect that was reversed by CD73i. Mechanistically, addition of AMP in MLRs repressed expression of activation markers and immune checkpoint proteins. Thus, activation of the adenosinergic pathway may limit the efficacy of ICI. TCGA data from anti-PD-1-treated melanoma patients identified CD73 expression as a negative prognostic factor. Finally, co-administration of a CD73i with an anti-PD-1 mAb resulted in significant reduction of tumor volume associated with increases in immune cell infiltration. CONCLUSIONS: CD73 inhibition, alone or in combination with anti-PD-1 and anti-TIGIT antibodies, translates into potent enhancement of immune cell activation in a variety of studies. These data provide a rationale for CD73i + ICI combinations. Citation Format: Annette Becker, Nell Narasappa, Fangfang Yin, Kristen Zhang, Daniel DiRenzo, Timothy Park, Jaroslaw Kalisiak, Ken Lawson, Jenna Jeffrey, Jay P. Powers, Ulrike Schindler, Matthew J. Walters, Joanne B. Tan. CD73 inhibitors (CD73i) reverse the AMP/adenosine-mediated impairment of immune effector cell activation by immune checkpoint inhibitors (ICI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 710.

Manipulation of tumor microenvironment by induction of immunogenic cell death and immune check point inhibitors for enhancing the efficacy of cancer treatments.

Introduction: Although immune checkpoint inhibitors (ICIs) have transformed cancer therapy, they can cause immune-related adverse effects, including ICI myocarditis, a potentially fatal form of inflammation-induced cardiac injury. What triggers autoreactive T cell activation in patients treated with ICIs remains unclear. Dendritic cells (DCs), which take up and present antigens to T cells for activation, could play a key role in the development of ICI myocarditis. Hypothesis: We hypothesize that reduced DC lysosomal activity in ICI myocarditis leads to reduced degradation of internalized antigens, preserving antigen epitopes and enhancing antigen presentation, leading to increased T cell activation. Methods: We have developed a mouse model of ICI myocarditis wherein three priming doses (100 mg/kg) of isoproterenol (ISO) followed by a high dose (300 mg/kg) of ISO provokes persistent autoreactive CD8+ T cell-driven myocarditis in mice deficient in the immune checkpoint inhibitor PD-1 (PD-1 KO). PD-1 KO mice have increased mortality and reduced cardiac function compared to wild-type mice. We studied DC lysosomes in this model in vivo (heart, mediastinal lymph nodes) and in vitro (bone marrow-derived DCs) using flow cytometry, biochemical tools, and mass spectrometry. Results: Using our ISO model, we observed that PD-1 KO DCs in the heart and mediastinal lymph nodes showed significantly reduced lysosomal acidification than wild-type in response to ISO priming. PD-1 KO bone marrow-derived DCs had significantly reduced cathepsin B activity and antigen processing capabilities than wild-type. Proteomic analyses of lysosomes isolated from antigen presenting cells in lymph nodes also showed increased cardiac peptide abundance in PD-1 KO DCs versus wild-type. Conclusions: Our findings demonstrate altered lysosomal degradation in PD-1 KO DCs. Future work will investigate how this affects antigen presentation, CD8+ T cell expansion, and cardiac outcomes in ICI myocarditis.

Immune checkpoint blockade (ICB) therapy has gained increasing attention due to its remarkable therapeutic performance. However, its therapeutic performance was highly impaired by the low immunogenicity of the tumors, insufficient intratumoral infiltration of the T lymphocytes, and the immunosuppressive tumor microenvironment. To address the challenge of current ICB therapy, nanosized drug delivery systems have been extensively exploited to deliver various immune modulators (e.g., chemotherapeutics, photosensitizers, and immune checkpoint inhibitors) for improved ICB therapy. In this review, we provide a brief overview of the recent advance of nanosized drug delivery systems for combination ICB immunotherapy. We also discuss the challenges and provide perspectives for the clinical translation of nanosized drug delivery systems for cancer immunotherapy.

The development of immune checkpoint inhibitors [monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1)] represents a major breakthrough in cancer therapy. Although they present a favorable risk/benefit ratio, immune checkpoint blockade therapies have a very specific safety profile. Due to their unique mechanism of action, they entail a new spectrum of adverse events that are mostly immune related [immune-related adverse events (irAEs)], notably mediated by the triggering of cytotoxic CD4+/CD8+T cell activation. Cutaneous toxicities appear to be one of the most prevalent irAEs, both with anti-PD-1 and anti-CTLA-4 agents or with the newly developed anti-PD-L1 agents, which corresponds to a class effect. They are observed in more than one-third of the treated patients, mainly in the form of a maculopapular rash (eczema-like spongiotic dermatitis) and pruritus. A wide range of other dermatologic manifestations can also occur, including lichenoid reactions, psoriasis, acneiform rashes, vitiligo-like lesions, autoimmune skin diseases (e.g., bullous pemphigoid, dermatomyositis, alopecia areata), sarcoidosis or nail and oral mucosal changes. In addition, the use of anti-CTLA-4 and anti-PD-1 therapies in combination is associated with the development of more frequent, more severe and earlier cutaneous irAEs compared to single agents. In most cases, these dysimmune dermatologic adverse events remain self-limiting and readily manageable. Early recognition and adequate management, however, are critical to prevent exacerbation of the lesions, to limit treatment interruption and to minimize quality of life impairment. This review describes the variable clinical and histopathologic aspects of dermatologic irAEs induced by immune checkpoint inhibitors. Appropriate treatment and counseling are also proposed, with a step-by-step approach for optimized management by both practicing oncologists and dermatologists.

Immune checkpoint blockade therapy (ICBT) targeting checkpoints, such as, cytotoxic T-lymphocyte associated protein-4 (CTLA-4), programmed death-1 (PD-1), or programmed death-ligand 1 (PD-L1), can yield durable immune response in various types of cancers and has gained constantly increasing research interests in recent years. However, the efficacy of ICBT alone is limited by low response rate and immune-related side effects. Emerging preclinical and clinical studies reveal that chemotherapy, radiotherapy, phototherapy, or other immunotherapies can reprogramm immunologically "cold" tumor microenvironment into a "hot" one, thus synergizing with ICBT. In this review, the working principle and current development of various immune checkpoint inhibitors are summarized, while the interactive mechanism and recent progress of ICBT-based synergistic therapies with other immunotherapy, chemotherapy, phototherapy, and radiotherapy in fundamental and clinical studies in the past 5 years are depicted and highlighted. Moreover, the potential issues in current studies of ICBT-based synergistic therapies and future perspectives are also discussed.

BackgroundHepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths worldwide, especially in advanced stages where limited treatment options result in poor prognosis. The immunosuppressive tumor immune microenvironment (TIME), characterized...

BackgroundThe immune response in the bone marrow microenvironment has implications for progression and prognosis in acute myeloid leukemia (AML). However, few immune‐related biomarkers for AML prognosis and immunotherapy response have been identified. We aimed to establish a predictive gene signature and to explore the determinants of prognosis in AML.MethodsImmune‐related genes with clinical significance were screened by a weighted gene co‐expression network analysis. Seven immune‐related genes were used to establish a gene signature by a multivariate Cox regression analysis. Based on the signature, low‐ and high‐risk groups were compared with respect to the immune microenvironment, immune checkpoints, pathway activities, and mutation frequencies. The tumor immune dysfunction and exclusion (TIDE) method was used to predict the response to immune checkpoint blockade (ICB) therapy. The Connectivity Map database was used to explore small‐molecule drugs expected to treat high‐risk populations.ResultsA seven‐gene prognostic signature was used to classify patients into high‐ and low‐risk groups. Prognosis was poorer for patients in the former than in the latter. The high‐risk group displayed higher levels of immune checkpoint molecules (LAG3, PD‐1, CTLA4, PD‐L2, and PD‐L1), immune cell infiltration (dendritic cells, T helper 1, and gamma delta T), and somatic mutations (NPM1 and RUNX1). Moreover, hematopoietic stem cell/leukemia stem cell pathways were enriched in the high‐risk phenotype. Compared with that in the low‐risk group, the lower TIDE score for the high‐risk group implied that this group is more likely to benefit from ICB therapy. Finally, some drugs (FLT3 inhibitors and BCL inhibitors) targeting the expression profiles associated with the high‐risk group were generated using Connectivity Map.ConclusionThe newly developed immune‐related gene signature is an effective biomarker for predicting prognosis in AML and provides a basis, from an immunological perspective, for the development of comprehensive therapeutic strategies.

The role of dendritic cells in asthma

Targeting the tumor microenvironment to overcome immune checkpoint blockade therapy resistance

Selective 5-Lipoxygenase Expression in Langerhans Cells and Impaired Dendritic Cell Migration in 5-LO-Deficient Mice Reveal Leukotriene Action in Skin

The chemokine system: tuning and shaping by regulation of receptor expression and coupling in polarized responses.

Cardiovascular diseases (CVDs) are one of the leading causes of mortality worldwide.1 It has been so for decades, notwithstanding a wide array of – mostly preventive – treatment modalities targeting known risk factors, such as hyperlipidemia, type 2 diabetes mellitus, hypertension, or obesity. Recent technical and conceptual advances have unveiled important contributions of the immune system in the pathophysiology of a variety of CVDs such as atherosclerosis, ischemic stroke, chronic heart failure, and other myocardial conditions like myocardial ischemia and reperfusion, viral myocarditis, and cardiac transplantation.2–4 In many of these disorders, so-called danger-associated molecular patterns (DAMPs), released from necrotic tissue and dying cells, can lead to the activation of certain immune cell populations such as monocytes/ macrophages, granulocytes, and T cells, thus aggravating ongoing inflammatory processes at the lesion site. Dendritic cells (DCs) are key modulators of immunity, pivotal in directing innate and adaptive immune responses against microbial, viral, but also modified self-antigens present at the sites of injury. Given the tissue trauma underlying various CVDs, it is not surprising that recent observations have allocated a regulatory role for DCs in CVD-associated immune responses. Interestingly, nondiseased arteries of young individuals were seen to host a network of resident vascular DCs (CD1a+ S100+ lag+ CD31− CD83− CD86−),5 representing a phenotype related to Langerhans cells in the skin. In agreement, monocyte-derived CD11c+ CD68+ dendritic cells could be detected in the atherosclerosis-prone lesser curvature and aortic sinus in inbred atherosclerosis-susceptible (C57Bl/6), but not resistant mouse strains (balb/c).6 Murine vascular resident DCs express an immature phenotype with low expression of costimulatory molecules, and are present in the subendothelial space with occasional probing into the vascular lumen. DCs have …

Immune therapies have significantly improved outcomes for cancer patients with poor prognosis, but mechanisms that underlie response or resistance to therapy remain elusive. Type I and Type II interferon signaling is required for immune activation but is also known to drive programs of tumor-intrinsic resistance. We propose that activation of pattern recognition receptor (PRR) signaling in specific cellular compartments underlies this seemingly contradictory observation. We have recently identified the highly structured RNA RN7SL1 (7SL) as a novel intratumoral PAMP (pathogen associated molecular pattern) capable of activating PRR signaling. When over-expressed in tumor cells, the resulting tumors are resistant to immune checkpoint blockade (ICB) therapy. However, 7SL is stimulatory to primary human DCs, and improves T cell priming in vitro. Furthermore, direct intratumoral injection of 7SL improves immune activation and response to ICB in vivo. Thus, we propose the localization of PAMP recognition and PRR signaling may represent an important determinant of response to ICB therapy. Based on this finding, we have developed a CAR T cell capable of producing 7SL in the tumor microenvironment, as well as a fully syngeneic B16 solid tumor model for CAR T cell therapy. Murine 7SL-CAR T cells control tumors more robustly than controls and synergize with ICB. Importantly, this effect is dependent on endogenous T cells, indicating that 7SL-CAR T cells are jump-starting an endogenous polyclonal anti-tumor immune response. In total, this represents a novel insight into the role of PRR signaling in tumors and leverages the findings to create a therapy with potential to serve patients that are currently refractory to CAR-T or ICB therapies alone.