Natural killer (NK) cells mediate innate immune responses against hazardous cells and are particularly important for the control of human cytomegalovirus (HCMV). NKG2D is a key NK activating receptor that recognizes a family of stress-induced ligands, including MICA, MICB, and ULBP1-6. Notably, most of these ligands are targeted by HCMV proteins and a miRNA to prevent the killing of infected cells by NK cells. A particular highly prevalent MICA allele, MICA008, is considered to be an HCMV-resistant "escape variant" that confers advantage to human NK cells in recognizing infected cells. However, here we show that HCMV uses its viral glycoprotein US9 to specifically target MICA008 and thus escapes NKG2D attack. The finding that HCMV evolved a protein dedicated to countering a single host allele illustrates the dynamic co-evolution of host and pathogen.

Background It was shown that immunocompromised patients have significantly reduced immunologic responses to COVID-19 vaccines. The immunogenicity of COVID-19 vaccine/infection in patients with solid tumors is reduced. We evaluated the immunologic response to COVID-19 and/or the BNT162b2 mRNA COVID-19 vaccine among cancer patients on active treatments and reviewed previous literature to identify subgroups that may require third vaccination. Patients and methods Anti-SARS-CoV-2 S1/S2 antibodies were measured in a cohort of 202 cancer patients on active treatment with chemotherapy (96), immunologic (52), biologic (46), and hormonal (12) treatments for early (n=66, 32.7%) or metastatic disease (n=136, 67.3%). Of those, 172 had received two vaccine doses, and 30 had COVID-19 infection (20/30 also received one dose of vaccine). Specific anti–S receptor-binding domain (RBD) antibodies were further measured in patients with equivocal anti S1/S2 results. Results Among cancer patients, the SARS-CoV-2 antibody response rate was 89.1% (180/202) after COVID-19 vaccination or infection and 87.2% (150/172) in patients after vaccination without a history of COVID-19, compared with 100% positive serologic tests in a control group of 30 healthcare workers (p<0.001). Chemotherapy treatment was independently associated with significantly reduced humoral response to infection or vaccination, with an 81.3% response rate, compared with 96.2% in patients on other treatments (p=0.001). In vaccinated patients on chemotherapy, the positive response rate was 77.5%. In a multiple regression model, a neutralizing antibody titer (>60 AU/ml) was more likely with immunotherapy (odds ratio 2.44) and less likely with chemotherapy (odds ratio 0.39). Conclusions Overall, both COVID-19 vaccine and natural infection are highly immunogenic among cancer patients. However, our study identifies those under chemotherapy as significantly less responsive, and with lower antibody levels. These findings justify close virological and serological surveillance along with consideration of these patients for booster (3rd dose) vaccine prioritization, as new highly spreading SARS-CoV-2 variants emerge.

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Author Contributions: Drs Rottenberg and Grinshpun had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Rottenberg and Grinshpun served as co-first authors.