Mechanism controlling tertiary lymphoid structure formation in tumors discovered

Date:
January 11, 2022
Source:
H. Lee Moffitt Cancer Center & Research Institute
Summary:
Tertiary lymphoid structures are formations that occur outside of
the lymphatic system. They contain immune cells and are similar
in structure and function to lymph nodes and other lymphoid
structures. However, little is known about how tertiary lymphoid
structures form. In a new article published in Immunity, Moffitt
Cancer Center researchers report on the molecular and cellular
mechanisms that control tertiary lymphoid structure formation
within tumors.



FULL STORY ========================================================================== Tertiary lymphoid structures are formations that occur outside of the
lymphatic system. They contain immune cells and are similar in structure
and function to lymph nodes and other lymphoid structures. However,
little is known about how tertiary lymphoid structures form. In a new
article published in Immunity, Moffitt Cancer Center researchers report
on the molecular and cellular mechanisms that control tertiary lymphoid structure formation within tumors.


==========================================================================
The immune system is composed of different types of cells and their
secreted proteins that regulate cancer development, including T cells and
B cells. T cells are further categorized according to their function and specific molecules they express, such as T follicular helper (Tfh) and
T follicular regulatory (Tfr) cells. Interactions among these different
immune cells can either contribute to or inhibit cancer development. Tfh
cells stimulate B cells to produce antibodies, while Tfr cells inhibit
this activity. Tfh and Tfr cells and other immune cells are found in in
the lymph nodes, as well as tertiary lymphoid structures.

Several studies have found better outcomes among patients with tumors
that have tertiary lymphoid structures, including superior responses to immunotherapy. It is speculated that the presence of active immune cells
within the tertiary lymphoid structures and their secreted proteins
contribute to immune activity against tumor cells. However, it is not
clear how tertiary lymphoid structures form, particularly since they
are rarely found in experimental mouse models.

Moffitt researchers performed a series of laboratory experiments with
cells and mouse models to improve their understanding of the molecular
and cellular mechanisms that lead to tertiary lymphoid structures
formation. They discovered that the protein SATB1 is an important
regulator of the differentiation process of Tfh and Tfr cells. SATB1
is a genomic organizing protein that helps to control how tightly DNA
is wound and serves as a recruiter for other modifying proteins. The researchers discovered that inhibiting the expression of SATB1 promotes
the differentiation process of Tfh cells and prevents the formation of
Tfr cells. They also identified some of the key contributing signaling molecules involved in this process, including ICOS and TGF-b.

The researchers confirmed the importance of SATB1 for this process by
showing that mice with T cells lacking SATB1 had a higher proportion
of Tfh cells that were able to interact with B cells and form tertiary
lymphoid structures within tumors. Importantly, the researchers also
showed that tumors grew less in mice that were injected with Tfh cells
when compared to control T cells, which was associated with the formation
of tertiary lymphoid structures within the tumors.

The researchers hope that their findings will lead to new interventions
to orchestrate tertiary lymphoid structures in irresectable tumors,
to support anticancer immunotherapies.

"Tertiary lymphoid structures are found in roughly 20% of human
cancers. Using the data from our study, we believe intratumoral
administration of autologous antigen specific Tfh cells in metastatic
cancers or unresectable tumors could promote the generation of tertiary lymphoid structures. The anti-tumor T cells found in those tertiary
lymphoid structures could provide a protective niche to exert immune
pressure against the progression of advanced malignancies and possibly
enhance the success of immunotherapies," said Jose Conejo-Garcia, M.D.,
Ph.D., chair of the Department of Immunology at Moffitt.

This study was supported by the National Cancer Institute (P30 CA076292).

========================================================================== Story Source: Materials provided by H._Lee_Moffitt_Cancer_Center_&_Research_Institute. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Ricardo A. Chaurio, Carmen M. Anadon, Tara Lee Costich, Kyle
K. Payne,
Subir Biswas, Carly M. Harro, Carlos Moran, Antonio C. Ortiz,
Carla Cortina, Kristen E. Rigolizzo, Kimberly B. Sprenger,
Jessica A. Mine, Patrick Innamarato, Gunjan Mandal, John J. Powers,
Alexandra Martin, Zhitao Wang, Sumit Mehta, Bradford A. Perez, Roger
Li, John Robinson, Jodi L. Kroeger, Tyler J. Curiel, Xiaoqing Yu,
Paulo C. Rodriguez, Jose R. Conejo-Garcia. TGF-b-mediated silencing
of genomic organizer SATB1 promotes Tfh cell differentiation and
formation of intra-tumoral tertiary lymphoid structures. Immunity,
2022; 55 (1): 115 DOI: 10.1016/ j.immuni.2021.12.007 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220111153640.htm

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