Immune checkpoint blockade (ICB) immunotherapy has revolutionized cancer treatment, demonstrating exceptional clinical responses in a wide range of cancers. Despite the success, a significant proportion of patients still fail to respond, highlighting the existence of unappreciated mechanisms of immunotherapy resistance. Delineating such mechanisms is paramount to minimize immunotherapy failures and optimize the clinical benefit.
In this study, we treated tumour-bearing mice with PD-L1 blockage antibody (aPD-L1) immunotherapy, to investigate its effects on cancer-induced emergency myelopoiesis, focusing on bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). We examined the impact of aPD-L1 treatment on HSPC quiescence, proliferation, transcriptomic profile, and functionality.
Herein, we reveal that aPD-L1 in tumour-bearing mice targets the HSPCs in the BM, mediating their exit from quiescence and promoting their proliferation. Notably, disruption of the PDL1/PD1 axis induces transcriptomic reprogramming in HSPCs, observed in both individuals with Hodgkin lymphoma (HL) and tumour-bearing mice, shifting towards an inflammatory state. Furthermore, HSPCs from aPDL1-treated mice demonstrated resistance to cancer-induced emergency myelopoiesis, evidenced by a lower generation of MDSCs compared to control-treated mice.
Our findings shed light on unrecognized mechanisms of action of ICB immunotherapy in cancer, which involves targeting of BM-driven HSPCs and reprogramming of cancer-induced emergency myelopoiesis.
Copyright © 2024 Boumpas, Papaioannou, Bousounis, Grigoriou, Bergo, Papafragkos, Tasis, Iskas, Boon, Makridakis, Vlachou, Gavriilaki, Hatzioannou, Mitroulis, Trompouki and Verginis.

Immune checkpoint blockade (ICB) immunotherapy has revolutionized cancer treatment, demonstrating exceptional clinical responses in a wide range of cancers. Despite the success, a significant proportion of patients still fail to respond, highlighting the existence of unappreciated mechanisms of immunotherapy resistance. Delineating such mechanisms is paramount to minimize immunotherapy failures and optimize the clinical benefit. Herein, we reveal that immunotherapy with PD-L1 blockage antibody (αPDL1) in tumour-bearing mice targets the hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (ΒΜ), mediating their exit from quiescence and promoting their proliferation. Notably, disruption of the PDL1/PD1 axis induces transcriptomic reprogramming in HSPCs, from both individuals with Hodgkin lymphoma (HL) and tumour-bearing mice shifting towards an inflammatory state. Functionally, transplantation of HSPCs isolated from αPDL1-treated tumor-bearing mice exhibited resistance to cancer-associated myelopoiesis as evident by the generation of reduced frequencies of myeloid-derived suppressor cells (MDSCs) compared to cells from control-treated mice. Our findings shed light on unrecognized mechanisms of action of ICB immunotherapy in cancer, which involves targeting of BM-driven HSPCs and reprogramming of emergency myelopoiesis.

Respiratory tract infection (RTI) is a leading cause of training and in-competition time-loss in athlete health. The immune factors associated with RTI susceptibility remain unclear. In this study, we prospectively characterise host immune factors in elite athletes exhibiting RTI susceptibility.
Peripheral blood lymphocyte flow cytometry phenotyping and 16S rRNA microbial sequencing of oropharyngeal swabs was performed in a prospective elite athlete cohort study (n = 121). Mass cytometry, peripheral blood mononuclear cell (PBMC) stimulation and plasma metabolic profiling was performed in age-matched highly-susceptible (HS) athletes (≥4RTI in last 18 months) (n = 22) compared to non-susceptible (NS) (≤1RTI in last 18 months) (n = 23) athletes. Findings were compared to non-athletic healthy controls (HC) (n = 19).
Athletes (n = 121) had a reduced peripheral blood memory T regulatory cell compartment compared to HC (p = 0.02 (95%CI:0.1,1.0)) and reduced upper airway bacterial biomass compared to HC (p = 0.032, effect size r = 0.19). HS athletes (n = 22) had lower circulating memory T regulatory cells compared to NS (n = 23) athletes (p = 0.005 (95%CI:-1.5,-0.15)) and HC (p = 0.002 (95%CI:-1.9,-0.3) with PBMC microbial stimulation assays revealing a T-helper 2 skewed immune response compared to HC. Plasma metabolomic profiling showed differences in sphingolipid pathway metabolites (a class of lipids important in infection and inflammation regulation) in HS compared to NS athletes and HC, with sphingomyelin predictive of RTI infection susceptibility (p = 0.005).
Athletes susceptible to RTI have reduced circulating memory T regulatory cells, metabolic dysregulation of the sphingolipid pathway and evidence of upper airway bacterial dysbiosis.
This study was funded by the English Institute of Sport (UK).
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Flow cytometric immunophenotyping is deemed a fundamental tool for the diagnosis of B-cell neoplasms. Currently, the investigation of novel immunophenotypic markers has gained importance, as they can assist in the precise subclassification of B-cell malignancies by flow cytometry. Therefore, the purpose of the present study was to evaluate the expression of CD307a during normal B-cell maturation and in B-cell malignancies as well as to investigate its potential role in the differential diagnosis of these entities.
CD307a expression was assessed by flow cytometry in normal precursor and mature B cells and in 115 samples collected from patients diagnosed with precursor and mature B-cell neoplasms. CD307a expression was compared between neoplastic and normal B cells.
B-acute lymphoblastic leukemia cases exhibited minimal expression of CD307a, displaying a similar expression pattern to that of normal B-cell precursors. Mantle cell lymphoma (MCL) cases showed the lowest levels of CD307a among mature B-cell neoplasms. CD307a expression was statistically lower in MCL cases than in chronic B lymphocytic leukemia (CLL) and marginal zone lymphoma (MZL) cases. No statistical differences were observed between CD307a expression in neoplastic and normal plasma cells.
These results indicate that the assessment of CD307a expression by flow cytometry could be helpful to distinguish CLL from MCL, and the latter from MZL. Although these results are not entirely conclusive, they provide a basis for further studies in a larger cohort of patients. © 2018 International Clinical Cytometry Society.
© 2018 International Clinical Cytometry Society.