Integrative analysis of spontaneous CLL regression highlights genetic and microenvironmental interdependency in CLL

Abstract

Spontaneous regression is a recognized phenomenon in chronic lymphocytic leukemia (CLL) but its biological basis remains unknown. We undertook a detailed investigation of the biological and clinical features of 20 spontaneous CLL regression cases incorporating phenotypic, functional, transcriptomic, and genomic studies at sequential time points. All spontaneously regressed tumors were IGHV-mutated with no restricted IGHV usage or B-cell receptor (BCR) stereotypy. They exhibited shortened telomeres similar to nonregressing CLL, indicating prior proliferation. They also displayed low Ki-67, CD49d, cell-surface immunoglobulin M (IgM) expression and IgM-signaling response but high CXCR4 expression, indicating low proliferative activity associated with poor migration to proliferation centers, with these features becoming increasingly marked during regression. Spontaneously regressed CLL displayed a transcriptome profile characterized by downregulation of metabolic processes as well as MYC and its downstream targets compared with nonregressing CLL. Moreover, spontaneous regression was associated with reversal of T-cell exhaustion features including reduced programmed cell death 1 expression and increased T-cell proliferation. Interestingly, archetypal CLL genomic aberrations including HIST1H1B and TP53 mutations and del(13q14) were found in some spontaneously regressing tumors, but genetic composition remained stable during regression. Conversely, a single case of CLL relapse following spontaneous regression was associated with increased BCR signaling, CLL proliferation, and clonal evolution. These observations indicate that spontaneously regressing CLL appear to undergo a period of proliferation before entering a more quiescent state, and that a complex interaction between genomic alterations and the microenvironment determines disease course. Together, the findings provide novel insight into the biological processes underpinning spontaneous CLL regression, with implications for CLL treatment.

Low Humoral Immune Response and Ineffective Clearance of SARS-Cov-2 in a COVID-19 Patient With CLL During a 69-Day Follow-Up

“…Our patient met the diagnostic IWCLL criteria. Monoclonal cells in CLL affect the phenotype and function of a variety of innate and adaptive immune cells, leading to an infection-prone environment and reduced immune surveillance ( 4 , 13 , 14 ). Studies have found humoral immune failure in CLL, which may be associated with hypogammaglobulinemia and IgG subclass deficiency ( 3 , 15 – 17 ), as CLL cells impair the immune system ( 18 ).…”

Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy

“…The similarities between CRS and systemic inflammatory response syndromes such as haemophagocytic lymphohistiocytosis and macrophage activation syndrome are discussed in Box 1 . Although these and other later-onset inflammatory toxicities have been observed independently of CAR T cell specificity, the published data suggest that they occur more frequently with CD22CAR T cells, which were developed to target tumour relapse secondary to CD19 antigen escape 30 – 32 .…”

Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies

“…Interestingly, patients with spontaneous regression show reduced T-cell exhaustion and increased T-cell proliferation, confirming the important role of the immune system in CLL progression. 91 Moreover, driver mutations are also present in these patients but they always remain stable without subclonal shifts. 91…”

“…91 Moreover, driver mutations are also present in these patients but they always remain stable without subclonal shifts. 91…”