Natural killer cell dysfunction is associated with colorectal cancer with severe COVID-19

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 induced coronavirus disease 2019 (COVID-19) has posed a great challenge to public health worldwide and also increased susceptibility to colorectal cancer (CRC). Natural killer (NK) cells serve as the first line of defense in the host's innate immune system, performing natural killing functions and mediating cytotoxicity against tumors and viruses. Therefore, a better understanding of NK cell cytotoxicity may facilitate the development of treatment strategies for CRC-associated with COVID-19.

Aim: To investigate the cytotoxic killing function of peripheral NK cells in patients with CRC and severe COVID-19 (CRC⁺ patients).

Methods: The percentages of circulating NK and NKT cells in CRC⁺ and age-matched patients with CRC were analyzed using flow cytometry. NK cell cytotoxic activity (NKCA) and corresponding NK cytotoxic factor (NKCF) activity in peripheral blood mononuclear cells were evaluated using a Real-Time Cell Analyzer.

Results: The numbers and percentage of peripheral NK and NKT cells in patients with CRC⁺ were lower than those in patients with CRC. Additionally, compared to patients with CRC, those with CRC⁺ had lower levels of NKCA and NKCF activity in lysed K562 cells. Positive correlations were observed between NKCA and NK cell numbers, NKCA and NK cell percentages, NKCF activity, and NK cell percentages in patients with CRC⁺. Furthermore, a negative correlation was observed between NKCA and the severity of COVID-19 in patients with CRC. The area under the receiver operating characteristic curve for NKCA was greater than those for the other indices.

Conclusion: CRC⁺ is associated with lower levels of peripheral NK cells and impaired natural cytotoxicity, contributing to the immunopathogenesis of severe COVID-19 rather than immune control.

Keywords: COVID-19; Colorectal cancer; Natural cytotoxicity; Natural killer cells; Natural killer cytotoxic factor.

Figure 1

Natural killer and natural killer T cells gating strategy from representative histogram of flow cytometric analysis. Graphs represented from left to right: Leukocyte population gating based on Side Scatter and Forward Scatter dot plot; leukocytes gating through Side Scatter and CD45; upper left quadrant represents CD3^-CD16/CD56⁺ natural killer (NK) cell population. upper right quadrant represents CD3⁺CD16/CD56⁺ NKT cell population.

Figure 2

Comparison of numbers and percentages of peripheral natural killer and natural killer T cells between colorectal cancer and colorectal cancer with severe the coronavirus disease 2019 patients. A: Representative histogram in peripheral blood of colorectal cancer (CRC) and CRC with severe the coronavirus disease 2019 (CRC⁺) patients; B: Comparison of natural killer (NK) and NKT cell numbers between CRC and CRC⁺ patients; C: Comparison of NK and NKT cell percentages between CRC and CRC⁺ patients. ^aP < 0.05 vs CRC⁺ via Student's t test; ^bP < 0.05 vs CRC⁺ via Mann-Whitney U test; CRC: Colorectal cancer; CRC⁺: Colorectal cancer with severe the coronavirus disease 2019; NK: Natural killer.

Figure 3

Comparison of natural killer cell cytotoxic activity and natural killer cytotoxic factor activity between colorectal cancer and colorectal cancer with severe the coronavirus disease 2019 patients. ^aP < 0.05 vs colorectal cancer with severe the coronavirus disease 2019 (CRC⁺) via Student's t test; ^bP < 0.01 vs CRC⁺ via Mann-Whitney U test; CRC: Colorectal cancer; CRC⁺: Colorectal cancer with severe the coronavirus disease 2019; NKCA: Natural killer cell cytotoxic activity; NKCF: Natural killer cytotoxic factor.

Figure 4

The correlation analysis between natural killer cells and natural killer cell cytotoxicity in colorectal cancer with severe the coronavirus disease 2019 patients. NK: Natural killer; NKCA: Natural killer cell cytotoxic activity; NKCF: Natural killer cytotoxic factor.

Figure 5

Receiver operating characteristic curve analysis of natural killer cells and natural killer cell cytotoxicity between colorectal cancer and colorectal cancer with severe the coronavirus disease 2019 patients. NK: Natural killer; NKCA: Natural killer cell cytotoxic activity; NKCF: Natural killer cytotoxic factor.