Description

Investigating the functions of tumor-associated tertiary lymphoid structures

Nikhil S Joshi

Yale University, Department of Immunobiology, New Haven, CT

The tumor microenvironment (TME) suppresses anti-tumor T cell responses, thereby allowing tumor progression. Yet, little is known about interactions between immune cells and early tumors, or how they lead to the immunosuppressive TME associated with advanced cancer. Autochthonous tumors in genetically-engineered mouse models (GEMMs) develop in their native tissue from individual cells, and in the presence of a fully-functional immune system. As tumor development mirrors human disease, GEMMs are ideally suited for investigating how the natural TME develops and how anti-tumor responses evolve throughout the disease course. In a neoantigen-expressing lung adenocarcinoma model, we found that >90% of tumors have tumor-associated tertiary lymphoid structures (TA-TLSs). TA-TLSs are common in lung cancer patients and strongly correlate with better disease outcomes. TA-TLSs in our model were functional immune organs, capable of recruiting circulating T cells and tumor-antigen presenting dendritic cells (DCs), and promoting local activation of tumor-specific T cells. Yet, immunosuppressive mechanisms within TA-TLSs including regulatory T cells (Tregs) promoted an overall state of immune quiescence, facilitating continued tumor growth. Acute Treg depletion led to rapid increases in lung-DC costimulatory molecule expression and T cell proliferation in TA-TLSs. Thereafter, tumors were dramatically infiltrated by immune cells, resulting in complete tumor destruction. These data support a model whereby apparent immune quiescence in advanced lung tumors belies ongoing immune processes within TA-TLSs. Local immune activation is balanced by immunosuppression, permitting continued tumor growth. However, therapeutic shifting of this balance unleashed powerful endogenous anti-tumor T cell responses that destroyed tumors. This highlights the ongoing importance of immunosuppression in the TME associated with advanced tumors and the potential therapeutic benefit of targeting immune cells in TA-TLSs.

Supported by 1K22CA200912-01.