Tertiary Lymphoid Structures: An Anti-tumor School for Adaptive Immune Cells and an Antibody Factory to Fight Cancer?

Jean-Luc Teillaud,Marie-Caroline Dieu-Nosjean

doi:10.3389/fimmu.2017.00830

Abstract

Tertiary lymphoid structures (TLS) present in human solid tumors are essential for the shaping of a favorable immune micro-environment to control tumor development in most cases. They represent a formidable school for T-cell priming, B cell activation, and differentiation into plasma cells and an exquisitely located factory for antibody production. The manipulation of TLS neogenesis and maintenance represents, therefore, an exciting task to set up efficient anti-cancer vaccine strategies leading to long-lasting anti-tumor adaptive responses. To achieve this goal, a number of important issues are still pending. How TLS-T and -B cells and antibodies locally produced are related to the improved survival of cancer patients with high density of TLS is still unclear. In addition, the mechanisms by which tumors escape the immune surveillance exerted by TLS are still poorly understood and the role of immune suppressive cytokines, regulatory T cells, and/or antibodies in this process remains to be explored. The identification of the key parameters that distinguish TLS with anti- or possible pro-tumor activity is also essential to make the therapeutic targeting of TLS a success. Finally, how TLS-based therapeutic approaches can be associated with targeted therapies or immunointerventions, such as the use of ICP blockers to improve anti-tumor responses, is an open question. We will discuss these different issues in the present review.

Highlights

In 2008, it was shown that lung tumors exhibit tertiary lymphoid structures (TLS) and that these structures correlate with a favorable clinical outcome in non-small-cell lung cancer (NSCLC) patients [1]
A number of reports have described the production of high-affinity anti-tumor antibodies, mostly IgG, by intra-tumoral B lymphocytes and animal models have made it possible to demonstrate the ability to these antibodies to impact tumor development [12,13,14,15]. These pre-clinical data have favored the idea that antibodies produced within the tumor masses through the generation of TLS contribute to the anti-tumor response, as already suggested by the correlation between the presence of plasma cells, IgG, or of kappa/lambda chains in tumors, and a more favorable outcome in breast cancer, NSCLC, colorectal cancer, metastatic melanoma, and ovarian cancer patients [16,17,18,19,20,21]
Since the discovery of the presence of TLS in human solid tumors [1], a large number of reports have highlighted the importance of these structures in the shaping of a favorable immune microenvironment capable of controlling tumor development in most cases [reviewed in Ref. [46]]

Summary

Introduction

In 2008, it was shown that lung tumors exhibit tertiary lymphoid structures (TLS) ( termed at that time tumor-induced bronchus-associated lymphoid tissues) and that these structures correlate with a favorable clinical outcome in non-small-cell lung cancer (NSCLC) patients [1]. Cancer-Associated TLS and B-Cell-Dependent Immunity zones are suggestive of the setting of a local antigen (Ag)-driven antibody response, which could lead to the production of antibodies with anti- or pro-tumor properties.

Results

Conclusion