Immune mechanisms in cancer patients that lead to poor outcomes of SARS-CoV-2 infection

Abstract

Patients with cancers have been severely affected by the COVID-19 pandemic. This is highlighted by the adverse outcomes in cancer patients with COVID-19 as well as by the impact of the COVID-19 pandemic on cancer care. Patients with cancer constitute a heterogeneous population that exhibits distinct mechanisms of immune dysfunction, associated with distinct systemic features of hot (T-cell-inflamed/infiltrated) and cold (Non-T-cell-inflamed and/or infiltrated) tumors. The former show hyper immune activated cells and a highly inflammatory environment while, contrastingly, the latter show the profile of a senescent and/or quiescent immune system. Thus, the evolution of SARS-CoV-2 infection in different types of cancers can show distinct trajectories which could lead to a variety of clinical and pathophysiological outcomes. The altered immunological environment including cytokines that characterizes hot and cold tumors will lead to different mechanisms of immune dysfunction, which will result in downstream effects on the course of SARS-CoV-2 infection. This review will focus on defining the known contributions of soluble pro- and anti-inflammatory mediators on immune function including altered T-cells and B-cells responses and as well on how these factors modulate the expression of SARS-CoV-2 receptor ACE2, TMPRSS2 expression, and lymph node fibrosis in cancer patients. We will propose immune mechanisms that underlie the distinct courses of SARS-CoV-2 infection in cancer patients and impact on the success of immune based therapies that have significantly improved cancer outcomes. Better understanding of the immune mechanisms prevalent in cancer patients that are associated to the outcomes of SARS-CoV-2 infection will help to identify the high-risk cancer patients and develop immune-based approaches to prevent significant adverse outcomes by targeting these pathways.

Fig 1

COVID-19 and its impact on development of immunity against SARS-CoV-2 infection. SARS-CoV-2 infect lung epithelial cells (1) and is sensed by macrophages and other innate immune cells (2). Upon sensing the SARS-CoV-2 infection, innate immune cells express cytokines (3) which accelerate the production of more cytokines and lead to cytokine storm (4). The resulting cytokine storm lead to dysregulation of immune functions and/or responses (5): dysregulated innate immune response (5.1), dysregulated adaptive immune response (5.2) – dysregulated T-cell response (a), dysregulated B-cell response (b), and dysregulated antibody response (c).

Fig 2

Changes in cancer cell signaling pathways upon Sars2 infection. Cancer (1) is heterogenous depending on the tumor micro environment: hot or cold (2), and the susceptibility of patients with cancer to SARS-CoV-2 infections (3) is influenced by cancer type. Four major signaling pathways that are common and impaired in both diseases are: cytokine, type-I IFN, androgen receptor, and immune checkpoint signaling pathways (4). These impairments in signaling pathways lead to cytokine storm that consequently ends up on acute respiratory distress syndrome (ARDS), organ failure, and death (5).

Fig 3

Mechanisms that lead to poor outcomes of COVID-19 in cancer patients. Cancer patients are highly heterogeneous population (A) and are divided into two major categories; hematological malignancies and solid tumors (B). Solid tumors can be further divided into hot tumor and cold tumor groups (C), which can get infected by SARS-CoV-2 (D) and develop COVID-19 (E). Course of infection of SARS-CoV-2 (1) – influenced by differential expression of ACE2 and TMPRSS2 in hot vs cold cancers – can lead to poor outcome of COVID-19 in hot vs cold cancer patients. Immune responses and development of immunity against SARS-CoV-2 (2) – influenced by differential innate (2.1) as well as adaptive (2.2) immune responses in hot vs cold cancers – can lead to poor outcome of COVID-19 in hot vs cold cancer patients. Impact of therapies (3) – influenced by immunotherapy as well as chemotherapy in hot vs cold cancers – can lead to poor outcomes of COVID-19 in hot vs cold cancer patients.

Fig 4

Treatments to enhance the immune response against SARS-CoV-2 infection in cancer patients. SARS-CoV-2 infect individuals with cancers (1) and SARS-CoV-2 infected individuals develop COVID-19 (2). COVID-19 vaccine is the first strategy to protect immunocompromised individuals, particularly cancer patients, from SARS-CoV-2 infection (3). Additional treatments are required for the cancer patients who cannot acquire protection, against COVID-19, through vaccine (4). Additional treatments include cytokine agonists (4.1): anti-IL-1 (a), anti-IL-6 (b), other immune modulators (c), and anti-PD-1 (4.2).