Intratumoral Lymphoid Aggregates May be Tertiary Lymphoid Structures

by Aliyah Weinstein

It’s well established in the field of immuno-oncology that in nearly all cancers, a subset of patients presents with an immune infiltrate. In many of these tumors, the infiltrating immune cells appear to form aggregates that are especially noticeable at the tumor periphery. Indeed, when presenting my research on these aggregates at scientific meetings, I’ve often been approached by other scientists or clinicians who indicate that they’ve seen lymphoid aggregates in tumor tissue from their patients, but didn’t know to investigate them further. 

This brief overview may change some of those minds.

These lymphoid aggregates have been termed tertiary (or “ectopic”) lymphoid organs, often referred to as TLS. First described about a decade ago, TLS develop at sites of chronic inflammatory responses, including cancer as well as chronic infection and autoimmune disease. They are now a growing area of investigation in immuno-oncology due to their prognostic value in numerous types of cancer; except in hepatocellular carcinoma, they predict extended progression-free and/or overall survival.

While multiparameter imaging can distinguish the features of TLS, they can more easily be appreciated by H&E staining. (Interestingly, a genetic signature based on chemokine expression can also be used to predict the presence of TLS within tumors.) TLS resemble secondary lymphoid organs based on the presence of a germinal center-like B cell aggregate and/or PNAd+ high endothelial venules surrounded by a zone of T cells and dendritic cells. Lymphocytes are recruited into TLS via these high endothelial venules, as PNAd binds L-selectin/CD62L, which is found on the surface of both T cells as well as B cells. TLS are thought to be a site of local T cell priming, independent of lymph nodes due to the ability of APC to recover antigen within the tissue and present it to nearby T cells within the TLS.

Besides their prognostic value, TLS may provide a novel avenue for therapeutic development. A recent publication from my lab demonstrated in a murine model of colon cancer that TLS can be induced therapeutically by the introduction of Type 1-polarized dendritic cells into the tumor microenvironment, and this is associated with delayed tumor growth. Others have postulated that TLS-positive tumors may be more responsive to immunotherapy because of the high density of T cell infiltrate in these tumors, including regulatory T cells.

An understanding by scientists and clinicians that lymphoid aggregates observed in tumors may have the hallmarks of TLS should help the field better appreciate in which tumor types they are found, and what their prognostic value may be. Simultaneously, while research into the benefit of therapeutically targeting TLS is still in its early stages, a basic understanding of these structures should help the field develop novel ways to target them therapeutically, while taking into account other characteristics such as tumor location, mutational status, and standard-of-care therapies for various cancers.