Impact of the Tumor Microenvironment on Progression and Treatment Response in Lymphoma and Chronic Lymphocytic Leukemia: A Systematic Review of the Literature.

in Critical reviews in oncology/hematology by Sebastian Villamizar Castellanos, Maria Paula Rodriguez Castellanos, Maria Camila Gil Avendaño, Mary Cielo Arias Asprilla, Miguel Santiago Garcia Leal, Gloria Tirado

TLDR

  • The study found that the tumor microenvironment (TME) plays a critical role in the progression and treatment response of lymphoma and chronic lymphocytic leukemia (CLL), with IL-6 and Tregs emerging as key biomarkers and therapeutic targets.
  • The findings suggest that targeting the TME, particularly Tregs, may optimize clinical outcomes, but methodological limitations persist and further research is needed.

Abstract

The tumor microenvironment (TME) plays a critical role in the progression of lymphomas and chronic lymphocytic leukemia (CLL). Comprising immune cells, cytokines, growth factors, and the extracellular matrix, it modulates therapeutic resistance and tumor aggressiveness. Key elements such as Tregs and TAMs induce immunosuppression, while cytokines like IL-6 promote malignant cell proliferation and survival. To synthesize evidence regarding the influence of the TME on the progression and treatment response in lymphoma and CLL, identifying knowledge gaps and potential therapeutic targets. A systematic review was conducted following PRISMA guidelines, including 17 studies published between 2000-2024 on the TME in lymphoma and CLL. Primary outcomes included overall survival (OS), progression-free survival (PFS), and treatment response rates. Searches included databases such as PubMed, Scopus, and Cochrane. Elevated IL-6 levels were associated with worse OS in aggressive lymphomas (mean OS 43.3 months in IL-6 positive patients vs. 96.0 months in negative, p < 0.001). A high proportion of Tregs in the TME correlated with shorter PFS (53% at 5 years vs. 72%, p = 0.013). In CLL, treatment with BTK inhibitors favorably modified the Th2/Th1 ratio (p < 0.002), improving clinical responses. The findings confirm the relevance of the TME as a determinant of clinical and prognostic heterogeneity. IL-6 and Tregs emerge as key biomarkers and therapeutic targets. Strategies aimed at reversing immunosuppression could optimize clinical outcomes; however, methodological limitations persist, such as heterogeneity in TME characterization methods.

Overview

  • The study aimed to investigate the influence of the tumor microenvironment (TME) on the progression and treatment response in lymphoma and chronic lymphocytic leukemia (CLL).
  • A systematic review was conducted including 17 studies published between 2000-2024 on the TME in lymphoma and CLL, following PRISMA guidelines.
  • Primary outcomes included overall survival (OS), progression-free survival (PFS), and treatment response rates, with a focus on identifying knowledge gaps and potential therapeutic targets.

Comparative Analysis & Findings

  • Elevated IL-6 levels were associated with worse overall survival (OS) in aggressive lymphomas, with a mean OS of 43.3 months in IL-6 positive patients compared to 96.0 months in negative patients (p < 0.001).
  • A high proportion of Tregs in the TME correlated with shorter progression-free survival (PFS), with a 5-year PFS rate of 53% compared to 72% in patients with lower Treg proportions (p = 0.013).
  • Treatment with BTK inhibitors favorably modified the Th2/Th1 ratio in CLL, improving clinical responses (p < 0.002).

Implications and Future Directions

  • The findings confirm the relevance of the TME as a determinant of clinical and prognostic heterogeneity, suggesting that IL-6 and Tregs emerge as key biomarkers and therapeutic targets.
  • Strategies aimed at reversing immunosuppression, such as targeting Tregs, may optimize clinical outcomes; however, methodological limitations persist, including heterogeneity in TME characterization methods.
  • Future studies should focus on developing targeted therapies that address the immunosuppressive TME, as well as exploring the impact of TME on treatment response and patient outcomes.
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