# Using virtual patient cohorts to uncover immune response differences in cancer and immunosuppressed COVID-19 patients

## TL;DR

Researchers used virtual patient models to study how cancer and immunosuppressed patients experience more severe immune responses during COVID-19.

## Contribution

The study introduces virtual patient cohorts to uncover immune response differences in cancer and immunosuppressed individuals with severe COVID-19.

## Key findings

- Severe cancer and immunosuppressed virtual patients had decreased CD8+ T cells and elevated IL-6 concentrations.
- Cancer patients showed higher viral loads due to neutropenia, but not directly linked to severity.
- Severe patients exhibited increased monocyte recruitment and lung tissue damage compared to reference groups.

## Abstract

The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulted in millions of deaths globally. Adults with immunosuppression (e.g., solid organ transplant recipients) and those undergoing active cancer treatments experience worse infections and more severe COVID-19. It is difficult to conduct clinical studies in these populations, resulting in a restricted amount of data that can be used to relate mechanisms of immune dysfunction to COVID-19 outcomes in these vulnerable groups. To study immune dynamics after infection with SARS-CoV-2 and to investigate drivers of COVID-19 severity in individuals with cancer and immunosuppression, we adapted our mathematical model of the immune response during COVID-19 and generated virtual patient cohorts of cancer and immunosuppressed patients. The cohorts of plausible patients recapitulated available longitudinal clinical data collected from patients in Montréal, Canada area hospitals. Our model predicted that both cancer and immunosuppressed virtual patients with severe COVID-19 had decreased CD8 + T cells, elevated interleukin-6 concentrations, and delayed type I interferon peaks compared to those with mild COVID-19 outcomes. Additionally, our results suggest that cancer patients experience higher viral loads (however, with no direct relation with severity), likely because of decreased initial neutrophil counts (i.e., neutropenia), a frequent toxic side effect of anti-cancer therapy. Furthermore, severe cancer and immunosuppressed virtual patients suffered a high degree of tissue damage associated with elevated neutrophils. Lastly, parameter values associated with monocyte recruitment by infected cells were found to be elevated in severe cancer and immunosuppressed patients with respect to the COVID-19 reference group. Together, our study highlights that dysfunctions in type I interferon and CD8 + T cells are key drivers of immune dysregulation in COVID-19, particularly in cancer patients and immunosuppressed individuals.

Individuals with active cancer disease and/or immunosuppression due to organ or stem cell transplantation often suffer from more severe COVID-19. These patients typically have CD8+ T cell deficiency and increased IL-6 concentrations, which is thought to weaken their immune response and increase their vulnerability to severe infections. To better predict COVID-19 severity in patients with cancer or immunosuppression, we paired a mechanistic mathematical model of the immune response to SARS-CoV-2 with clinical data from these patients. Comparing their predicted model trajectories to those from a reference COVID-19 virtual patient cohort suggested that cancer patients tend to have higher viral load peaks compared to other patients, which our model predicted to be due to pre-existing neutropenia. In addition, both immunosuppressed and cancer virtual patients exhibited increased monocyte recruitment and overall more lung tissue damage than those in the reference group. The main severity indicators in all virtual patients were found to be a delayed type I IFN peak and depressed CD8 + T cell concentrations, particularly in cancer and immunosuppressed patients. However, our model predicted that neutrophils were substantially increased only in severe cancer and immunosuppressed patients. Together, this study uses virtual patient cohorts in complement to experimental and clinical studies to better understand the immunological dysregulation leading to severe COVID-19 in vulnerable patient groups.