SARS coronavirus 2 (SARS-CoV-2) is a novel viral pathogen that causes a clinical disease called coronavirus disease 2019 (COVID-19). Although most COVID-19 cases are asymptomatic or involve mild upper respiratory tract symptoms, a significant number of patients develop severe or critical disease. Patients with severe COVID-19 commonly present with viral pneumonia that may progress to life-threatening acute respiratory distress syndrome (ARDS). Patients with COVID-19 are also predisposed to venous and arterial thromboses that are associated with a poorer prognosis. The present study identified the emergence of a low-density inflammatory neutrophil (LDN) population expressing intermediate levels of CD16 (CD16 Int ) in patients with COVID-19. These cells demonstrated proinflammatory gene signatures, activated platelets, spontaneously formed neutrophil extracellular traps, and enhanced phagocytic capacity and cytokine production. Strikingly, CD16 Int neutrophils were also the major immune cells within the bronchoalveolar lavage fluid, exhibiting increased CXCR3 but loss of CD44 and CD38 expression. The percentage of circulating CD16 Int LDNs was associated with D-dimer, ferritin, and systemic IL-6 and TNF-α levels and changed over time with altered disease status. Our data suggest that the CD16 Int LDN subset contributes to COVID-19–associated coagulopathy, systemic inflammation, and ARDS. The frequency of that LDN subset in the circulation could serve as an adjunct clinical marker to monitor disease status and progression.

It has long been understood that the control and surveillance of tumors within the body involves an intricate dance between the adaptive and innate immune systems. At the center of the interplay between the adaptive and innate immune response sits the complement system—an evolutionarily ancient response that aids in the destruction of microorganisms and damaged cells, including cancer cells. Membrane-bound complement regulatory proteins (mCRPs), such as CD46, CD55, and CD59, are expressed throughout the body in order to prevent over-activation of the complement system. These mCRPs act as a double-edged sword however, as they can also over-regulate the complement system to the extent that it is no longer effective at eliminating cancerous cells. Recent studies are now indicating that mCRPs may function as a biomarker of a malignant transformation in numerous cancer types, and further, are being shown to interfere with anti-tumor treatments. This highlights the critical roles that therapeutic blockade of mCRPs can play in cancer treatment. Furthermore, with the complement system having the ability to both directly and indirectly control adaptive T-cell responses, the use of a combinatorial approach of complement-related therapy along with other T-cell activating therapies becomes a logical approach to treatment. This review will highlight the biomarker-related role that mCRP expression may have in the classification of tumor phenotype and predicted response to different anti-cancer treatments in the context of an emerging understanding that complement activation within the Tumor Microenvironment (TME) is actually harmful for tumor control. We will discuss what is known about complement activation and mCRPs relating to cancer and immunotherapy, and will examine the potential for combinatorial approaches of anti-mCRP therapy with other anti-tumor therapies, especially checkpoint inhibitors such as anti PD-1 and PD-L1 monoclonal antibodies (mAbs). Overall, mCRPs play an essential role in the immune response to tumors, and understanding their role in the immune response, particularly in modulating currently used cancer therapeutics may lead to better clinical outcomes in patients with diverse cancer types.

As the SARS-CoV-2 virus wreaks havoc on the populations, health care infrastructures and economies of nations around the world, finding ways to protect health care workers and bolster immune responses in the general population while we await an effective vaccine will be the difference between life and death for many people. Recent studies show that innate immune populations may possess a form of memory, termed Trained Immunity (TRIM), where innate immune cells undergo metabolic, mitochondrial, and epigenetic reprogramming following exposure to an initial stimulus that results in a memory phenotype of enhanced immune responses when exposed to a secondary, heterologous, stimulus. Throughout the literature, it has been shown that the induction of TRIM using such inducers as the BCG vaccine and β-glucan can provide protection through altered immune responses against a range of viral infections. Here we hypothesize a potential role for β-glucan in decreasing worldwide morbidity and mortality due to COVID-19, and posit several ideas as to how TRIM may actually shape the observed epidemiological phenomena related to COVID-19. We also evaluate the potential effects of β-glucan in relation to the immune dysregulation and cytokine storm observed in COVID-19. Ultimately, we hypothesize that the use of oral β-glucan in a prophylactic setting could be an effective way to boost immune responses and abrogate symptoms in COVID-19, though clinical trials are necessary to confirm the efficacy of this treatment and to further examine differential effects of β-glucan's from various sources.

Macrophages use mitochondrial lactate metabolism for ACLY-dependent histone acetylation, immune suppression, and tumor progression.

An increased understanding of the complex mechanisms at play within the tumor microenvironment (TME) has emphasized the need for the development of strategies that target immune cells within the TME. Therapeutics that render the TME immune-reactive have a vast potential for establishing effective cancer interventions. One such intervention is β-glucan, a natural compound with immune-stimulatory and immunomodulatory potential that has long been considered an important anti-cancer therapeutic. β-glucan has the ability to modulate the TME both by bridging the innate and adaptive arms of the immune system and by modulating the phenotype of immune-suppressive cells to be immune-stimulatory. New roles for β-glucan in cancer therapy are also emerging through an evolving understanding that β-glucan is involved in a concept called trained immunity, where innate cells take on memory phenotypes. Additionally, the hollow structure of particulate β-glucan has recently been harnessed to utilize particulate β-glucan as a delivery vesicle. These new concepts, along with the emerging success of combinatorial approaches to cancer treatment involving β-glucan, suggest that β-glucan may play an essential role in future strategies to prevent and inhibit tumor growth. This review emphasizes the various characteristics of β-glucan, with an emphasis on fungal β-glucan, and highlights novel approaches of β-glucan in cancer therapy.