Distinct immune composition in lymph node and peripheral blood of CLL patients is reshaped during venetoclax treatment

Abstract

Morbidity and mortality due to immunosuppression remain among the foremost clinical challenges in chronic lymphocytic leukemia (CLL). Although immunosuppression is considered to originate within the lymph node (LN) microenvironment, alterations in T and natural killer (NK) cells have almost exclusively been studied in peripheral blood (PB). Whereas chemoimmunotherapy further deteriorates immune function, novel targeted agents like the B-cell lymphoma 2 inhibitor venetoclax potentially spare nonmalignant lymphocytes; however, the effects of venetoclax on nonleukemic cells have not been explored. We address these unresolved issues using a comprehensive analysis of nonmalignant lymphocytes in paired LN and PB samples from untreated CLL patients, and by analyzing the effects of venetoclax-based treatment regimens on the immune system in PB samples from previously untreated and relapsed/refractory patients. CLL-derived LNs contained twice the amount of suppressive regulatory T cells (Tregs) and CLL supportive follicular T helper (Tfh) cells compared with PB. This was accompanied by a low frequency of cytotoxic lymphocytes. The expression of PD-1 by CD8+ T cells was significantly higher in LN compared with PB. Venetoclax-based treatment led to deep responses in the majority of patients, but also to decreased absolute numbers of B, T, and NK cells. Tfh cell, Treg, and PD-1+ CD8+ T cell numbers were reduced more than fivefold after venetoclax-based therapy, and overproduction of inflammatory cytokines was reduced. Furthermore, we observed restoration of NK cell function. These data support the notion that the immunosuppressive state in CLL is more prominent within the LN. Venetoclax-based regimens reduced the immunosuppressive footprint of CLL, suggesting immune recovery after the elimination of leukemic cells.

Deciphering The Complex Circulating Immune Cell Microenvironment in Chronic Lymphocytic Leukemia Using Patient Similarity Networks

“…Importantly, the activation of all immune cells in the majority of our patients receiving novel drugs was more pronounced compared with those previously treated with immunochemotherapy or untreated patients, even after correction for CLL cell number. In line with our data, a recent study using venetoclax-based regimens revealed a reduction in the immunosuppressive footprint of CLL, suggesting that immune system regeneration occurs after removal of leukemic cells [45]. Similarly, ibrutinib has been shown to modulate the immunosuppressive CLL microenvironment, through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway [46].…”

“…The crucial impact of CLL bulk on blood microenvironment observed in our study is also supported by a recent study showing that CLL cells impair mitochondrial fitness in CD8+ T cells and impede CAR T-cell efficacy [29]. Also other studies showed that CLL cells are active participants in microenvironmental cross-talk [30] contributing to the inhibition of effective immune cell activation by production of spectrum of immunosuppressive mediators [12,31,32], most prominently in the lymph nodes [31]. Here we provide evidence of the immunosuppressive condition also in circulation in CLL.…”

“…Ibrutinib and idelalisib have been shown to have an immunomodulatory effect on T cells [5,13,39,40,41,42], NK cells [43], monocytes [13], and production of Th2 cytokines [44], depending on the time of treatment [13]. Also venetoclax has been shown to modulate number and activation of T and B cells, restore NK cell function and reduce overproduction of inflammatory cytokines [45]. In our study, multivariate analyses revealed activation of all circulating immune cells in the majority of patients treated with novel drugs.…”

EOMES and IL-10 regulate anti-tumor activity of PD-1+CD4+T-cells in B-cell Non-Hodgkin lymphoma

“…Moreover, we noted a population of EOMES + PD-1 + CD4 + T-cells in LN samples of CLL as well as DLBCL patients. In the follicles of secondary lymphoid organs, tight interactions of T- and malignant B-cells take place, which lead to activation and, in case of persistent exposure to antigens, to T-cell exhaustion (37, 47) which might contribute to the observed phenotype of T-cells in CLL and DLBCL LNs.…”

Management of CLL patients early in the COVID‐19 pandemic: An international survey of CLL experts

“…2 Therapeutic agents for CLL have immunomodulatory effects that can potentially alter the risk of contracting and the response to infection. 3,4 The interface of SARS-CoV-2 infection, severity of COVID-19 symptoms, and active treatment of CLL represents a major therapeutic dilemma-should CLL-directed therapy continue or be held? This is particularly true for patients receiving B-cell receptor kinase inhibitors, where abrupt treatment discontinuation can result in rapid decompensation in some patients that could mimic COVID-I9 symptoms.…”