Toward Patient-Specific Therapies for Advanced Cutaneous T Cell Lymphoma

Cutaneous T cell lymphomas (CTCL) are a group of T lymphocyte malignancies that mainly affect the skin. Early diagnosis of CTCL is difficult due to a lack of highly specific markers for malignant lymphocytes. In its early stages, CTCL progresses slowly, is treatable, and has a good prognosis. However, patients with advanced-stage CTCL have few treatment options available, reflecting continued poor understanding of the disease’s origins and development. Due to the absence of markers for CTCL, diagnosis typically occurs about seven years after symptom onset, preventing timely treatment and resulting in poorer clinical outcomes. 

In the spring of 2019, pharmaceutical chemist Patrizia Fuschiotti, PhD, published new findings in Clinical Cancer Research on single-cell analysis of CTCL skin-tumor samples using droplet-based single-cell CTCL skin biopsies. The study describes patient-specific lymphocyte heterogeneity and identifies specific markers that pave the way for early diagnosis of and development of patient-specific therapies for CTCL.

Dr. Fuschiotti completed her doctoral work in pharmaceutical chemistry at the University of Perugia, Italy, before joining the Division of Rheumatology and Clinical Immunology at the University of Pittsburgh School of Medicine as an assistant professor in 2009. Her research interests focus on the cellular and molecular mechanisms of pathogenesis by T cell and T cell-derived cytokines in chronic inflammatory conditions. 

In particular, she has examined the roles played by the cytokine interleukin-13 (IL-13) and its receptors (IL-13Ra1 and IL-13Ra2) in fibrosis, autoimmunity, and cancer in the context of human diseases that affect the skin. Dr. Fuschiotti has shown that IL-13 and its molecular pathways are involved in both systemic sclerosis, an autoimmune connective tissue disease whose main clinical feature is fibrosis, and CTCL. In addition to understanding the underlying mechanisms of pathogenesis, Dr. Fuschiotti has been developing strategies for targeting IL-13 and its molecular pathways to provide therapeutic relief.

Laying the Groundwork for Personalized Medicine

Dr. Fuschiotti’s current work investigates CTCL skin-tumor heterogeneity with the aim of developing therapeutic strategies tailored to specific patients, aided by the use of novel single-cell RNA sequencing technology applied to a 3 mm screen biopsy. Explaining the technology’s value for physicians, she says, “It gives a more patient-specific feature of the disease, for developing patient-specific therapy.” This lays the groundwork for personalized medicine and is therefore very topical. 

The Clinical Cancer Research study found patterns of gene expression that were unique for each patient, as well as a common gene-expression signature for the disease itself — findings that are important for the future development of both CTCL-specific and patient-specific drug therapies, says Dr. Fuschiotti.

The 3 mm screen biopsy yielded a huge amount of information on all the cell types present within the biopsied tissue, providing a general picture of lymphocytes — both malignant and nonmalignant — as well as of other cell types present within the microenvironment that are important because they produce proteins that enhance tumor growth and suppress the immune response against the tumor. 

The study found vast heterogeneity not only among tumors but also within each tumor. This diversity may ultimately point the way to the development of patient-specific therapies for CTCL. 
“For example, we have identified that in one patient there was activation partly associated with the tumor invasion. In another patient there was a strong inflammatory component that was similar to psoriasis. These activated patient-specific pathways suggest that therapies need to be tailored to individual patients,” says Dr. Fuschiotti. 

Identifying Markers of Tumor Proliferation

An additional very important finding from the study was that some signatures were common to most patients with advanced-stage CTCL and were markers of tumor proliferation. A critical problem in diagnosing and treating CTCL is that it is difficult to identify malignant cells from healthy reactive T cells because no marker has been identified for this. In its early stages, CTCL tumors are indolent and difficult to find — a key reason for delayed diagnosis of CTCL. Validated markers of tumor proliferation could potentially be used to diagnose CTCL earlier in the disease course.
Another finding addresses the character of the reactive lymphocytes that are often found infiltrating CTCL skin tumors. These lymphocytes differ in their ability to respond to and reject tumors. 
“We saw that within different patients the reactive lymphocytes express different types of checkpoint inhibitory receptors. Not all of the patients expressed these receptors, and some patients may express more than one. So, we have demonstrated an important tumor cell heterogeneity that may affect how patients respond to cancer immunotherapy, requiring personalized approaches to be developed,” says Dr. Fuschiotti. 

Another current direction of work in Dr. Fuschiotti’s lab is focused on potential CTCL prevention strategies. In 2015, in a paper published in Blood, Dr. Fuschiotti and her colleagues uncovered how IL-13 modulates tumor proliferation or growth. 

Following up on that work, Dr. Fuschiotti is now working on interfering with IL-13’s signaling pathways and collaborating with a pharmaceutical company, Regeneron, to determine whether a novel antibody targeting the IL-13 receptor can block cell proliferation that leads to the development of CTCL. 

In a related project, supported by a CLARIONS Research Grant from the Cutaneous Lym-phoma Foundation, the team is following up on an observation that malignant T lymphocytes in CTCL express the IL-13 alpha 1 and alpha 2 receptor subunits and is examining whether targeting a molecule located downstream from IL-13 activation can block lymphocyte proliferation. 

References

Gaydosik AM, Tabib T, Geskin LJ, Bayan CA, Conway JF, Lafyatis R, Fuschiotti P. Single-cell Lymphocyte Heterogeneity in Advanced Cutaneous T-Cell Lymphoma Skin Tumors. Clin Cancer Res. 2019
Jul 15; 25(14): 4443-4454.
Geskin LJ, Viragova S, Stolz DB, Fuschiotti P. Interleukin-13 Is Overexpressed in Cutaneous T-cell Lymphoma Cells and Regulates Their Proliferation. Blood. 2015 Apr 30; 125(18): 2798-2805.
Further Reading
Fuschiotti P, Larregina AT, Ho J, Feghali-Bostwick C, Medsger Jr TA. Interleukin–13–producing CD8+ T Cells Mediate Dermal Fibrosis in Patients With Systemic Sclerosis. Arthritis & Rheumatism. 2013
Jan; 65(1): 236-246.
Wasik MA. IL-13 as a Novel Growth Factor in CTCL. Blood. 2015 Apr 30; 125(18): 2737-2738.