Cancer patients, particularly with hematologic malignancies, remain a vulnerable cohort for COVID-19 disease caused by SARS-CoV-2. In primary infection studies, hematologic cancer patients exhibited a distinct immune cell signature vs. solid tumor cancer patients. However, prolonged viral shedding was observed in both hematologic & solid cancer patients, while some cleared infection adequately. Studies have also shown impaired serologic vaccine responses in hematologic cancer patients. It remains unclear whether differential biological pathway perturbations in hematologic & solid cancer responses to either primary infection (infection cohort) or to primary COVID-19 vaccination (vaccine cohort) may explain these discrepancies.

To address this, we utilised LC-MS PBMC proteomics, flow cytometry & blood counts, assessing 6 patient groups: an infection cohort (short & long viral shedders) & a vaccine cohort (solid / hematologic cancer patients with / without serologic COVID-19 vaccine response). Infection samples were taken at first positive SARS-CoV-2 RT-PCR; short shedders (n=5) cleared virus within 14 days, while prolonged shedders (n=13) did not. Proteomics data were available for 4 short and 9 prolonged shedders & were compared to 17 COVID negative cancer controls. For the vaccine cohort, we analysed proteomic changes from baseline to 3 weeks post–first dose in 16 haematologic & 15 solid cancer patients. Responders were defined by anti-Spike IgG EC50 >70.

Within the infection cohort, prolonged shedders exhibited higher eosinophil counts & increased CD103+VD1 gd T % & TIM3+PD1+ / PD1+Naïve CD4+ T % compared to short shedders (p<0.05). Proteomic analysis of COVID+ patients (irrespective of shedder status) vs. COVID- patients revealed alterations including CRP & KRT1(adj.p<0.05). SERPINA1 was upregulated in short shedders(log2FC=0.86,adj.p<0.05) but not prolonged(log2FC=0.04,adj.p=0.97). α1AT has been shown to block SARS-CoV-2 viral entry & replication in cell lines & primary human airway cells. Gene set enrichment analysis revealed that inflammatory response, fatty acid metabolism, TNFa, coagulation & complement pathways were upregulated in short shedders, not prolonged.

Within the vaccine cohort responders, coagulation, humoral, complement & B cell pathways were upregulated. However, this collective profile was driven differently in solid vs hematologic patients. Hematologic responders upregulated coagulation, platelet activation & hemostasis, solid responders did not. Both groups activated classical complement (C1Q, C1R, C4A/B), but their downstream profiles differed. Hematologic responders upregulated CFP & CLU, consistent with an innate-skewed alternate complement response while solid patients did not. B cell related pathways were only upregulated in solid responders, likely reflecting that 62.5% of hematologic patients were on treatment for B cell malignancies.

We next performed comparative pathway analysis across 6 groups to assess whether differential immune responses to vaccination mirrored those seen after infection. Solid vaccine responders exhibited classical complement & B cell pathway protein engagement including CD19, MYD88, suggesting intact coordination between innate & adaptive immunity. Hematologic vaccine responders upregulated classical & alternative complement pathways with enrichment of ‘B cell–mediated immunity’ pathway; however, lacked expression of CD19, MYD88, instead increased IL21R indicating incomplete B cell development. Hematologic vaccine non-responders also did not upregulate CD19, MYD88 instead expressing ERCC1, HSPD1, LIG4, RIF1, MSH6 suggesting cellular stress. Short shedders activated complement & lacked B cell pathway upregulation, whereas prolonged shedders showed active downregulation of B cell activation & BCR signalling, with no complement engagement.

In conclusion, these data indicate that hematologic cancer patients in particular are associated with impaired coordination between innate & adaptive immunity following SARS-CoV-2 exposure. This immune dysregulation, observed after infection & vaccination, may underlie increased clinical vulnerability. Indeed, prolonged shedders & hematologic vaccine non-responders show blunted immune activation. Notably, even hematologic vaccine responders exhibit a dysregulated profile, with complement activation but lacking B cell recovery, suggesting that apparent serological response may not equate to full immune competence in this group.

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2025
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