The novel 2019 strain of coronavirus is a source of profound morbidity and mortality worldwide. Compared with recent viral outbreaks, COVID-19 infection has a relatively high mortality rate, the ...reasons for which are not entirely clear. Furthermore, treatment options for COVID-19 infection are currently limited. In this Perspective, we explore the contributions of the innate and adaptive immune systems to both viral control as well as toxicity during COVID-19 infections and offer suggestions to both understand and therapeutically modulate anti-COVID immunity.
The metabolic reprogramming associated with malignant transformation has led to a growing appreciation of the nutrients required to support anabolic cell growth. Less well studied is how cancer cells ...satisfy those demands in vivo, where they are dispersed within a complex microenvironment. Tumor-associated stromal components can support tumor growth by providing nutrients that supplement those provided by the local vasculature. These non-malignant stromal cells are phenotypically similar to those that accumulate during wound healing. Owing to their immediate proximity, stromal cells are inevitably affected by the metabolic activity of their cancerous neighbors. Until recently, a role for tumor cell metabolism in influencing the cell fate decisions of neighboring stromal cells has been underappreciated. Here, we propose that metabolites consumed and released by tumor cells act as paracrine factors that regulate the non-malignant cellular composition of a developing tumor by driving stromal cells toward a regenerative response that supports tumor growth.
The concept of tumor stromal cells supporting tumor growth by providing nutrients has gained growing appreciation in recent years. In this review, Schwörer et al. discuss how the metabolic activity of cancer cells contributes to converting various stromal cell types into promoting a regenerative response that supports tumor growth.
Treatment paradigms for B-cell non-Hodgkin lymphomas (B-NHL) have shifted dramatically in the last 2 decades following the introduction of highly active immunotherapies such as rituximab. Since then, ...the field has continued to witness tremendous progress with the introduction of newer, more potent immunotherapeutics, including chimeric antigen receptor T-cell therapy, which have received regulatory approval for and currently play a significant role in the treatment of these diseases. Bispecific antibodies (BsAb) are a novel class of off-the-shelf T-cell redirecting drugs and are among the most promising immunotherapeutics for lymphoma today. BsAb may target various cell-surface antigens and exist in different formats. Anti-CD20xCD3 BsAb have demonstrated remarkable single-agent activity in patients with heavily pretreated B-NHL with a manageable toxicity profile dominated by T-cell overactivation syndromes. Much work remains to be done to define the optimal setting in which to deploy these drugs for B-NHL treatment, their ideal combination partners, strategies to minimize toxicity, and, perhaps most importantly, pharmacodynamic biomarkers of response and resistance. In this review, we provide an update on BsAb development in B-NHL, from discovery to clinical applications, highlighting the achievements, limitations, and future directions of the field.
Classical Hodgkin lymphoma is curable in the majority of cases with chemotherapy and/or radiation. However, 15-20% of patients ultimately relapse and succumb to their disease. Pathologically, ...classical Hodgkin lymphoma is characterized by rare tumor-initiating Reed-Sternberg cells surrounded by a dense immune microenvironment. However, the role of the immune microenvironment, particularly T and B cells, in either promoting or restricting Classical Hodgkin lymphoma growth remains undefined. Recent dramatic clinical responses seen using monoclonal antibodies against PD-1, a cell surface receptor whose primary function is to restrict T cell activation, have reignited questions regarding the function of the adaptive immune system in classical Hodgkin lymphoma. This review summarizes what is known regarding T cells, B cells, and immune checkpoints in classical Hodgkin lymphoma.
The cancer-immunity cycle (CIC) comprises a series of events that are required for immune-mediated control of tumor growth. Interruption of one or more steps of the CIC enables tumors to evade ...immunosurveillance. However, attempts to restore antitumor immunity by reactivating the CIC have had limited success thus far. Recently, numerous studies have implicated metabolic reprogramming of tumor and immune cells within the tumor microenvironment (TME) as key contributors to immune evasion. In this opinion, we propose that alterations in cellular metabolism during tumorigenesis promote both initiation and disruption of the CIC. We also provide a rationale for metabolically targeting the TME, which may assist in improving tumor responsiveness to chimeric antigen receptor (CAR)-transduced T cells or immune checkpoint blockade (ICB) therapies.
Elevated tumor glycolysis and lactate production are robust suppressors of antitumor immunity in multiple cancer subtypes.Loss of mitochondrial function is a hallmark of CD8+ T cell exhaustion and might be a promising metabolic target for improving patient responses to CAR-T and/or ICB therapy, pending future investigations.IL4I1-driven tryptophan catabolism and aryl hydrocarbon receptor activation may constitute a resistance mechanism to ICB and/or IDO1 inhibitors across cancer subtypes.We propose that the metabolic profile of the TME promotes both initiation and disruption of the cancer-immunity cycle. Hence, targeting cellular metabolism in the TME may improve responsiveness to T cell-based immunotherapies.
Cancer patients, especially those with hematologic malignancies, are at increased risk for coronavirus disease 2019 (COVID-19)-related complications and mortality. We describe the incidence, clinical ...characteristics, risk factors, and outcomes of persistent COVID-19 infection in patients with hematologic malignancies.
The syndrome of persistent COVID-19 in patients with hematologic malignancies manifests as a chronic protracted illness marked by waxing and waning or progressive respiratory symptoms and prolonged viral shedding. Immunosuppressed patients with lymphoid malignancies may serve as partially immune reservoirs for the generation of immune-evasive viral escape mutants.
Persistent COVID-19 infection is a unique concern in patients with hematologic malignancies. While vaccination against severe acute respiratory syndrome coronavirus 2 has reduced the overall burden of COVID-19 in patients with hematologic cancers, whether vaccination or other novel treatments for COVID-19 prevent or alleviate this syndrome remains to be determined.
The majority of tumor-infiltrating T cells exhibit a terminally exhausted phenotype, marked by a loss of self-renewal capacity. How repetitive antigenic stimulation impairs T cell self-renewal ...remains poorly defined. Here, we show that persistent antigenic stimulation impaired ADP-coupled oxidative phosphorylation. The resultant bioenergetic compromise blocked proliferation by limiting nucleotide triphosphate synthesis. Inhibition of mitochondrial oxidative phosphorylation in activated T cells was sufficient to suppress proliferation and upregulate genes linked to T cell exhaustion. Conversely, prevention of mitochondrial oxidative stress during chronic T cell stimulation allowed sustained T cell proliferation and induced genes associated with stem-like progenitor T cells. As a result, antioxidant treatment enhanced the anti-tumor efficacy of chronically stimulated T cells. These data reveal that loss of ATP production through oxidative phosphorylation limits T cell proliferation and effector function during chronic antigenic stimulation. Furthermore, treatments that maintain redox balance promote T cell self-renewal and enhance anti-tumor immunity.
How primary tumors alter distant tissue sites to facilitate seeding and metastasis remains unclear. In this issue, Gong et al. demonstrate that IL-1β-dependent lipid accumulation in lung mesenchymal ...cells supports both tumor growth and NK cell dysfunction, facilitating lung metastasis of primary breast tumors.
Coronavirus disease 2019 (COVID-19) infection results in both acute mortality and persistent and/or recurrent disease in patients with hematologic malignancies, but the drivers of persistent ...infection in this population are unknown. We found that B-cell lymphomas were at particularly high risk for persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity. Further analysis of these patients identified discrete risk factors for initial disease severity compared with disease chronicity. Active therapy and diminished T-cell counts were drivers of acute mortality in COVID-19-infected patients with lymphoma. Conversely, B cell-depleting therapy was the primary driver of rehospitalization for COVID-19. In patients with persistent SARS-CoV-2 positivity, we observed high levels of viral entropy consistent with intrahost viral evolution, particularly in patients with impaired CD8
T-cell immunity. These results suggest that persistent COVID-19 infection is likely to remain a risk in patients with impaired adaptive immunity and that additional therapeutic strategies are needed to enable viral clearance in this high-risk population. SIGNIFICANCE: We describe the largest cohort of persistent symptomatic COVID-19 infection in patients with lymphoid malignancies and identify B-cell depletion as the key immunologic driver of persistent infection. Furthermore, we demonstrate ongoing intrahost viral evolution in patients with persistent COVID-19 infection, particularly in patients with impaired CD8
T-cell immunity.
.
PDF
