The Tumor Microenvironment as a Therapeutic Target in Cutaneous T Cell Lymphoma

Abstract

Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin lymphomas, with mycosis fungoides and Sézary syndrome being the two common subtypes. Despite the substantial improvement in early-stage diagnosis and treatments, some patients still progress to the advanced stage with an elusive underpinning mechanism. While this unsubstantiated disease mechanism coupled with diverse clinical outcomes poses challenges in disease management, emerging evidence has implicated the tumor microenvironment in the disease process, thus revealing a promising therapeutic potential of targeting the tumor microenvironment. Notably, malignant T cells can shape their microenvironment to dampen antitumor immunity, leading to Th2-dominated responses that promote tumor progression. This is largely orchestrated by alterations in cytokines expression patterns, genetic dysregulations, inhibitory effects of immune checkpoint molecules, and immunosuppressive cells. Herein, the recent insights into the determining factors in the CTCL tumor microenvironment that support their progression have been highlighted. Also, recent advances in strategies to target the CTCL tumor micromovement with the rationale of improving treatment efficacy have been discussed.

Keywords: Sézary syndrome; cutaneous T cell lymphoma; cytokines; genetic alterations; immune checkpoints; mycosis fungoides; tumor microenvironment.

Figure 1

CTCL TME negatively regulates the tumor immune microenvironment to support CTCL progression. Immune cells infiltrating the CTCL tumor microenvironment promote angiogenesis, tumor growth, migration, and immunosuppression.

Figure 2

Role of cancer-associated fibroblasts in CTCLs. Cancer-associated fibroblasts promote CTCL migration, growth, apoptosis resistance, and immunosuppression.

Figure 3

Contribution of endothelial cells to CTCLs. Endothelial cells promote angiogenesis, tumor metastasis, growth, and apoptosis resistance.

Figure 4

Molecular mechanisms of CTCL progression: CTCL TME influences the malignant transformation of CTCLs through genetic alterations, apoptosis resistance, immune checkpoint-mediated immunosuppression, cytokine dysregulations, and exosome secretions.