Harnessing Tertiary Lymphoid Structures for Improved Immunotherapeutic Strategies in Cancer Patients

Endeavor Award (2022-Present)

University of Pittsburgh and UPMC Hillman Cancer Center: Tullia C. Bruno, PhD • The University of Texas MD Anderson Cancer Center: Tina Cascone, MD, PhD; Kevin McBride, PhD; Jennifer Wargo, MD, MMSc • Yale University School of Medicine: Nikhil Joshi, PhD; Aaron Ring, MD, PhD

Tullia Bruno, PhD

Tina Cascone, MD, PhD

Kevin McBride, PhD

Jennifer Wargo, MD, MMSc

Nikhil Joshi, PhD

Aaron Ring, MD, PhD

The different cell types of the immune system continuously interact with each other to mount a robust response to foreign organisms and neoplastic cells. Over the past decade, tremendous progress has been made in developing cancer therapeutics which harness the power of the immune system. Despite these advances, the promise of the immunotherapy revolution has not yet been fully realized. Only a subset of patients responds to immunotherapy, and new strategies are needed to increase the response rate. A more comprehensive examination of the interactions of various components of the immune system as well as the tumor will be critical in improving the success of immunotherapy.

This Endeavor team, whose expertise is spread across a wide range of disciplines, will examine how tertiary lymphoid structures (TLS) affect the development and treatment of tumors. In normal lymphoid tissues such as the spleen and lymph nodes, TLS are complex formations of B cells, T cells, and antigen-presenting cells in close proximity which signal to each other in a process that is critical for developing an immune response. In some cancer patients, de novo TLS at various stages of maturity develop near the site of the tumor and are associated with better prognosis and tumor control. Although their importance is clear, the mechanistic basis for the formation of these tumor-associated TLS and their precise role in controlling tumor progression are poorly understood.

The team will examine how distinct tumor microenvironments drive TLS heterogeneity by comparing three different solid tumors: melanoma, head and neck squamous cell carcinoma, and non-small cell lung cancer, utilizing cutting-edge spatial transcriptomics paired with evaluation of key environmental drivers within these tumors. They will also examine how TLS heterogeneity impacts tumor-specific antibody production by intratumoral B cells. Finally, they will probe how TLS heterogeneity is impacted by immunotherapy by interrogating TLS profiles in longitudinal samples from immunotherapy-treated cohorts. Critically, for all of these studies the team will use both clinical specimen and state-of-the-art mouse models to cross correlate their findings.

This Endeavor team brings together a group of investigators with expertise in different cutting-edge methods, including spatial transcriptomics, immunofluorescence, microbiome metagenomics, mouse modeling, and data analysis. This integrated team approach will allow them to gain an understanding of the influence and opportunity of TLS in cancer, and will be key in advancing immunotherapies to reach more patients.