Unravelling soluble immune checkpoints in chronic lymphocytic leukemia: Physiological immunomodulators or immune dysfunction

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.

Programmed Death 1 and Cytotoxic T-Lymphocyte-Associated Protein 4 Gene Expression in Peripheral Blood Mononuclear Cells Can Serve as Prognostic Biomarkers for Hepatocellular Carcinoma

“…As demonstrated in this study, conventional serum biomarkers (e.g., AFP, AST, and ALT) are suboptimal for estimating the survival of HCC patients. Exploring more relevant serum proteins, such as sPD-1, sCTLA-4, sPD-L1, sTIM-3, sBTLA, sVISTA, and sLAG-3, in addition to examining their gene expression levels in PBMCs, may help identify effective serum markers for predicting the survival outcomes of HCC patients [31,32]. Previously, we quantified mRNA and protein expression and established a multimodal analysis platform [22].…”

The Role of CXCL11 and its Receptors in Cancer: Prospective but Challenging Clinical Targets

“… 36 The mutation status of the immunoglobulin heavy chain variable region (IGHV-mutated) is a prognostic biomarker related to CLL, and CXCL11 is significantly associated with CLL. 37 CXCL11 can also serve as a diagnostic and progression prediction factor for diffuse large B-cell lymphoma. Zhou et al found that CXCL11 is expressed more in patients with later-stage DLBCL and has a high diagnostic prediction ability (AUC = 1.000).…”

Beyond the anti-PD-1/PD-L1 era: promising role of the BTLA/HVEM axis as a future target for cancer immunotherapy

“…In solid tumors, elevated levels of sBTLA in sera have been associated with decreased survival and aggressive disease in prostate and ovarian cancer, pancreatic adenocarcinoma, clear cell renal cancer, and hepatocellular carcinoma, among others [71,[93][94][95][96]. Circulating sBTLA levels have also been detected in patients with CLL [89,97]. Indeed, increased sBTLA levels were associated with aggressive behavior and decreased time to treatment in these patients [89].…”