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Unravelling soluble immune checkpoints in chronic lymphocytic leukemia: Physiological immunomodulators or immune
Alicia Landeira-Viñuela1, Carlota Arias-Hidalgo1, Pablo Juanes-Velasco1
1Department of Medicine and General Service of Cytometry, Centro de Investigación Biomédica en Red Cáncer (CIBERONC)- CB16/12/00400, Cancer Research Centre-Instituto Universitario de Biología Molecular y Celular del Cáncer (IBMCC), Consejo Superior de Investigaciones Científicas - Universidad de Salamanca (CSIC-USAL), Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
Insights
This study profiles 103 serum proteins in chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBLhi) patients. Soluble immune factors identified can serve as biomarkers for CLL diagnosis, progression, and prognosis.
Area of Science:
- Hematology
- Immunology
- Oncology
Background:
- Chronic lymphocytic leukemia (CLL) is a heterogeneous lymphoid neoplasm with complex immune system dysregulation and tumor microenvironment interactions.
- Prognostic factors in CLL include IGHV mutational status, del17p, and TP53 mutations, highlighting genetic heterogeneity.
- Immune surveillance is impacted in CLL, influencing disease onset, evolution, and therapy response.
Purpose of the Study:
- To quantitatively profile 103 serum proteins, including cytokines, chemokines, immune checkpoints, and soluble receptors, in CLL and MBLhi patients.
- To identify differential profiles of soluble immune factors that distinguish between MBLhi and CLL, predict disease progression, and correlate with prognostic factors like IGHV mutational status.
Main Methods:
- Systematic quantitative profiling of 103 serum proteins was performed.
- Serum samples from 57 CLL patients and 10 MBLhi individuals were analyzed.
- Differential expression analysis was conducted to identify key soluble immune factors.
Main Results:
- Specific soluble immune factors (sCD47, sCD27, sTIMD-4, sIL-2R, sULBP-1) differentiated MBLhi from CLL.
- Other factors (sCD48, sCD27, sArginase-1, sLAG-3, IL-4, sIL-2R) correlated with disease progression.
- Factors including CXCL11/I-TAC, CXCL10/IP-10, sHEVM, and sLAG-3 were associated with IGHV mutational status.
Conclusions:
- Soluble immune checkpoints represent promising biomarkers for CLL diagnosis, prognosis, and monitoring.
- These findings offer insights into immune suppression and T-cell dysfunction in CLL.
- Understanding immune factor profiles can elucidate microenvironment polarization and tumor escape mechanisms in CLL.
Abstract:
Chronic lymphocytic leukemia (CLL) is a lymphoid neoplasm characterized by the accumulation of mature B cells. The diagnosis is established by the detection of monoclonal B lymphocytes in peripheral blood, even in early stages [monoclonal B-cell lymphocytosis (MBLhi)], and its clinical course is highly heterogeneous. In fact, there are well-characterized multiple prognostic factors that are also related to the observed genetic heterogenicity, such as immunoglobulin heavy chain variable region (IGHV) mutational status, del17p, and TP53 mutations, among others. Moreover, a dysregulation of the immune system (innate and adaptive immunity) has been observed in CLL patients, with strong impact on immune surveillance and consequently on the onset, evolution, and therapy response. In addition, the tumor microenvironment is highly complex and heterogeneous (i.e., matrix, fibroblast, endothelial cells, and immune cells), playing a critical role in the evolution of CLL. In this study, a quantitative profile of 103 proteins (cytokines, chemokines, growth/regulatory factors, immune checkpoints, and soluble receptors) in 67 serum samples (57 CLL and 10 MBLhi) has been systematically evaluated. Also, differential profiles of soluble immune factors that discriminate between MBLhi and CLL (sCD47, sCD27, sTIMD-4, sIL-2R, and sULBP-1), disease progression (sCD48, sCD27, sArginase-1, sLAG-3, IL-4, and sIL-2R), or among profiles correlated with other prognostic factors, such as IGHV mutational status (CXCL11/I-TAC, CXCL10/IP-10, sHEVM, and sLAG-3), were deciphered. These results pave the way to explore the role of soluble immune checkpoints as a promising source of biomarkers in CLL, to provide novel insights into the immune suppression process and/or dysfunction, mostly on T cells, in combination with cellular balance disruption and microenvironment polarization leading to tumor escape.
