ABSTRACT
Cancer patients are at increased risk for critical illness upon COVID-19. We assessed antibody and T cell responses in unexposed and SARS-CoV-2 convalescent cancer patients to characterize SARS-CoV-2 immunity and to identify immunological parameters contributing to increased morbidity and mortality in COVID-19 cancer patients. Immune responses were assessed in unexposed (n = 199) and SARS-CoV-2-infected cancer patients (n = 17), comprising different hematological malignancies (HM) and solid tumor entities. T cell responses were assessed by IFN-g ELISPOT using previously defined cross-reactive and SARS-CoV-2-specific T cell epitopes (Nelde et al., Nat Immunol 2021). SARS-CoV-2 convalescents without cancer (n = 193) and unexposed healthy volunteers (HV, n = 94) served as reference groups. Whereas pre-existing SARS-CoV-2 cross-reactive CD4+ T cell responses were detectable in a high proportion of HV (78%) and solid tumor patients (77%), frequency was substantially lower in unexposed HM patients (34%). Concordantly, HM patients showed significantly higher proportions of CD4+ T cells expressing PD-1, LAG-3 and TIM-3, indicating T cell exhaustion as a potential underlying cause for the reduced T cell reactivity. In SARS-CoV-2 convalescents, no difference in antibody positivity was noted between cancer patients and HV. T cell response analyses showed comparable recognition frequencies of SARS-CoV-2-specific HLA class I and HLA-DR epitopes in both groups, whereas the frequency of HLA-DR cross-reactive T cell responses was significantly reduced in cancer patients. Again, this was attributable to a markedly reduced frequency of cross-reactive CD4+ T cell responses in HM patients. Analysis of T cell responses to single HLA-DR peptides (n = 20) after 12-day in vitro expansion further revealed reduced T cell expandability for 73% of SARS-CoV-2-derived peptides in COVID-19 cancer patients. Moreover, diversity of SARS-CoV-2 T cell responses (i.e. recognition of multiple different T cell epitopes) was significantly reduced in COVID-19 HM patients (20% recognized peptides) compared to solid tumor patients (35%) and HV (50%), and reduced T cell diversity was associated with a more severe course of COVID-19. In summary, our results identify impaired SARS-CoV-2 T cell immunity as a determinant for poor outcome of COVID-19 in cancer patients, particularly in HM. These findings guide the development of therapeutic measures and vaccines for this vulnerable patient population. Disclosure: Malte Roerden: No conflict of interest disclosed. Juliane S. Walz: Honoraria: Juliane S. Walz is listed as inventor for patents on peptides described in the research.;Expert Testimony: Bundesministerium für Bildung und Forschung (BMBF), German Cancer Consortium (DKTK), Deutsche Forschungsgemeinschaft (DFG), Wilhelm Sander Stiftung, José Carreras Leukämie-Stiftung, Fortüne-Programm der Universität Tübingen.