The Impact of SARS-CoV-2 Infection on Cancer: An In-depth Review

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The coronavirus disease 2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has posed an unprecedented global health challenge.

This viral infection has exhibited a wide clinical spectrum, ranging from asymptomatic cases to severe respiratory failure and death (Parasher, 2021). It primarily spreads through respiratory droplets during close contact, making it a highly contagious virus (Wiersinga et al., 2020).

Beyond its immediate health consequences, recent research has raised concerns about the potential long-term impact of SARS-CoV-2 infection on cancer development. This review aims to comprehensively explore the available data regarding the relationship between SARS-CoV-2 infection and cancer, including the effects on signal transduction pathways, immune surveillance, chronic inflammation, oxidative stress, cell cycle dysregulation, and potential viral genome integration.

Additionally, we will analyze the potential impact of antiviral therapy used in COVID-19 treatment on oncogenesis and cancer progression.

Mortality Among SARS-CoV-2-Infected Patients

The emergence of the COVID-19 pandemic has led to significant mortality worldwide. Estimates suggest a mean in-hospital mortality rate of approximately 15%-20%, rising to 40% among patients admitted to the Intensive Care Unit (ICU) (Wiersinga et al., 2020).

Shockingly, the number of excess deaths due to SARS-CoV-2 infections is nearly three times higher than documented by official statistics, underscoring the gravity of the pandemic (COVID-19 Excess Mortality Collaborators, 2022).

Several underlying health conditions, including obesity, diabetes, hypertension, cancer, and respiratory and cardiovascular diseases, increase the risk of severe COVID-19 outcomes and mortality (Gallo Marin et al., 2021). Notably, cancer patients infected with SARS-CoV-2 face significantly higher mortality rates than non-cancer patients, with mortality ranges spanning from 11.4% to 35.5% (Ali et al., 2022).

The Impact of SARS-CoV-2 Infection on Cancer Outcomes

Influence on Immune Response

SARS-CoV-2 has a profound impact on the host’s immune response, which in turn can affect cancer outcomes.

The interaction between SARS-CoV-2 infection and cancer immunotherapy, such as immune checkpoint inhibitors, introduces complexities in managing both conditions. Furthermore, lymphopenia induced by cancer treatments, including chemotherapy, radiotherapy, and steroid therapy, coupled with an elevated ratio of neutrophils to lymphocytes, serve as poor prognostic indicators for both cancer progression and the course of COVID-19 (Ali et al., 2022).

Inflammation and Cancer Progression

Inflammation plays a pivotal role in both cancer development and SARS-CoV-2 infection. The release of inflammatory cytokines, including IL-6 and tumor necrosis factor-alpha (TNF-alpha), is a common link between cancer and inflammation.

These same cytokines are markedly elevated in SARS-CoV-2 infection, suggesting a possible intersection of cancer and inflammation pathways (De Winter et al., 2021). Notably, cancer-promoting growth factors have been observed in patients with hematological malignancies up to three months after SARS-CoV-2 infection, highlighting the potential for long-term consequences (De Winter et al., 2021).

Mortality Rates and SARS-CoV-2 Infection in Cancer Patients

Studies have consistently demonstrated higher mortality rates in cancer patients infected with SARS-CoV-2 compared to those without cancer. A study involving 500,000 American adults with COVID-19 revealed a 7.8% mortality rate among recently treated cancer patients, whereas patients with non-recently treated cancer had a 5.0% mortality rate, and those without cancer had a 1.6% mortality rate (Chavez-MacGregor et al., 2022).

A meta-analysis of 29 studies involving 21,257 patients with lung cancer and SARS-CoV-2 infection indicated significantly higher mortality rates among these patients than in those without cancer (Oldani et al., 2022). Moreover, an Italian study found a substantially higher proportion of deaths among patients with cancer infected with SARS-CoV-2 compared to those without cancer (Rugge et al., 2020).

Treatment Challenges

SARS-CoV-2 infection has disrupted cancer treatment, causing delays, permanent discontinuations, and the inability to perform scheduled diagnostic procedures (Tagliamento et al., 2020). The impact of asymptomatic or mildly symptomatic SARS-CoV-2 infection on cancer treatment outcomes is not well understood. Limited case reports suggest that asymptomatic infection may not necessarily contraindicate chemotherapy, but data on the long-term effects are lacking (Woźniak et al., 2021). Alarmingly, asymptomatic or mild SARS-CoV-2 infection in children with cancer, particularly those with hematological malignancies, has been associated with a higher risk of death compared to cancer patients without infection (Hazarika et al., 2022).

SARS-CoV-2: Anti-Tumour Immunity and Immune Escape (IE)

Emerging evidence suggests that SARS-CoV-2 infection may impact the immune surveillance of cancer, potentially leading to an increased risk of cancer development (Jafarzadeh et al., 2022). CD8+ cytotoxic lymphocytes and CD4+ lymphocytes are key players in the antitumor immune response.

CD8+ T cells can eliminate cancer cells when they recognize specific antigens, while CD4+ T cells regulate the antitumor response by modulating immune activities.

However, SARS-CoV-2 infection has been associated with lymphopenia, reduced numbers of CD4+ and CD8+ T cells, and impaired natural killer (NK) cell function, particularly in severe cases (O’Connell and Aldhamen, 2020). This immune dysfunction, characterized by increased inhibitory receptor NKG2A expression, can lead to decreased production of cytokines and diminished cytotoxic activity of CD8+ T and NK cells, mirroring immune responses seen in some cancer types (Jafarzadeh et al., 2022). NKG2A, when bound with CD94, can suppress the effector functions of T and NK cells, reducing their anticancer efficacy (André et al., 2018).

Immune escape (IE) is a phenomenon where cancer cells avoid elimination by the immune system. Viruses can enhance IE, leading to an impaired host immune response to both the infectious agent and cancer. Various mechanisms have been observed in other viruses, such as HCV, influenza A virus, and SARS-CoV, which can affect immune surveillance.

SARS-CoV-2 also exhibits mechanisms that influence immune surveillance, including dysregulation of interferon production, cytokine release, dendritic cell, macrophage, NK, and neutrophil function (Chakraborty et al., 2022). However, the precise relationship between SARS-CoV-2 infection and cancer immune surveillance remains incompletely understood (Liapis and Baritaki, 2022).

DAMP (Damage-Associated Molecular Pattern) and PAMP (Pathogen-Associated Molecular Pattern) – A Possible Link Between SARS-CoV-2 Infection and Oncogenesis

Antigenic stimulation initiated by DAMPs and PAMPs in both cancer and infectious diseases shares similarities. Innate immunity, the first line of defense against viral infections, recognizes PAMPs and DAMPs through pattern recognition receptors (PRRs) (Li and Wu, 2021). NK cells play a vital role in defending against SARS-CoV-2 infection, releasing cytotoxic granules, participating in antibody-dependent cellular cytotoxicity, and producing cytokines and chemokines that can eliminate infected cells (Ma et al., 2021).

Infected cells can undergo inflammatory cell death and release DAMPs, such as viral nucleic acids and oligomers, leading to inflammation, increased reactive oxygen and nitrogen species, tissue damage, apoptosis, and potential malignant transformation (Hotchkiss and Moldawer, 2014). The hypoxic microenvironment created by inflammation can also induce oxidative stress, promoting tumor invasion and migration (Ye et al., 2020).

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that promote cancer cell growth, inhibit immune responses mediated by NK and T cells, and induce fibrosis, hypoxia, and changes in the extracellular matrix (Chauhan et al., 2013).

Interestingly, SARS-CoV-2 enters cells through ACE receptors, downregulating ACE enzyme activity and enhancing the angiotensin type 2-ATR1 axis (Hoffmann et al., 2020). Components of the renin-angiotensin-aldosterone system (RAAS), including CAFs, are also expressed in the TME, suggesting potential interactions between SARS-CoV-2 infection and the tumor microenvironment (Wu et al., 2020).

Cytokine Storm and Inflammation: A Double-Edged Sword

SARS-CoV-2 infection can lead to a cytokine storm, an exaggerated immune response characterized by the release of large amounts of proinflammatory cytokines. This excessive inflammation can cause severe tissue damage, multiorgan failure, and potentially promote cancer development. On the other hand, chronic inflammation, such as that seen in viral infections, has long been associated with an increased risk of cancer (Colotta et al., 2009).

The proinflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-α) are often elevated in both severe COVID-19 cases and various cancer types.

They can contribute to an immunosuppressive microenvironment that supports cancer growth and metastasis (Liapis and Baritaki, 2022). Additionally, the activation of the nuclear factor-kappa B (NF-κB) pathway during inflammation can promote cell proliferation, angiogenesis, and resistance to apoptosis, all of which are hallmarks of cancer (Karin and Greten, 2005).

On the other hand, the cytokine storm associated with severe COVID-19 may enhance the immune system’s ability to recognize and eliminate cancer cells. High levels of cytokines can attract immune cells to the site of infection or tumor, potentially enhancing immune surveillance (Liapis and Baritaki, 2022).

Conclusion

The complex interplay between SARS-CoV-2 infection and cancer is a subject of growing concern and research. The available evidence suggests that cancer patients are at a significantly higher risk of severe COVID-19 outcomes and mortality. Inflammation, immune response alterations, and treatment disruptions due to SARS-CoV-2 infection can influence cancer progression and outcomes. As the world continues to grapple with the COVID-19 pandemic, it is imperative to prioritize the management and protection of cancer patients, both in terms of infection prevention and ensuring uninterrupted cancer care. Further research is needed to fully understand the long-term implications of SARS-CoV-2 infection on cancer development and treatment outcomes.


reference link : https://www.frontiersin.org/articles/10.3389/fmolb.2023.1260776/full

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