Spatial characterization of tertiary lymphoid structures as predictive biomarkers for immune checkpoint blockade in head and neck squamous cell carcinoma
(1) Ruiz-Torres DA (2) Bryan ME (3) Hirayama S (4) Merkin RD (5) Luciani E (6) Roberts TJ (7) Patel M (8) Park JC (9) Wirth LJ (10) Sadow PM (11) Sade-Feldman M (12) Stott SL (13) Faden DL
(1) Ruiz-Torres DA (2) Bryan ME (3) Hirayama S (4) Merkin RD (5) Luciani E (6) Roberts TJ (7) Patel M (8) Park JC (9) Wirth LJ (10) Sadow PM (11) Sade-Feldman M (12) Stott SL (13) Faden DL
Immune checkpoint blockade (ICB) is the standard of care for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), yet efficacy remains low. The combined positive score (CPS) for PD-L1 is the only biomarker approved to predict response to ICB and has limited performance. Tertiary Lymphoid Structures (TLS) have shown promising potential for predicting response to ICB. However, their exact composition, size, and spatial biology in HNSCC remain understudied. To elucidate the impact of TLS spatial biology in response to ICB, we utilized pre-ICB tumor tissue sections from 9 responders (complete response, partial response, or stable disease) and 11 non-responders (progressive disease) classified via RECISTv1.1. A custom multi-immunofluorescence (mIF) staining assay was applied to characterize tumor cells (pan-cytokeratin), T cells (CD4, CD8), B cells (CD19, CD20), myeloid cells (CD16, CD56, CD163), dendritic cells (LAMP3), fibroblasts (_ Smooth Muscle Actin), proliferative status (Ki67) and immunoregulatory molecules (PD1). A machine learning model was employed to measure the effect of spatial metrics on achieving a response to ICB. A higher density of B cells (CD20+) was found in responders compared to non-responders to ICB (p_=_0.022). The presence of TLS within 100_µm of the tumor was associated with improved overall (p_=_0.04) and progression-free survival (p_=_0.03). A multivariate machine learning model identified TLS density as a leading predictor of response to ICB with 80% accuracy. Immune cell densities and TLS spatial location play a critical role in the response to ICB in HNSCC and may potentially outperform CPS as a predictor of response.
Author Info:
(1) Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, USA. Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer
Center, Boston, MA, USA. Department of Medicine, Harvard Medical School, Boston MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (2) Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (3) Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, USA. (4) Department of Medicine, Harvard Medical School, Boston MA, USA. Department of Medicine, Center for Head and Neck Cancers, Massachusetts General Hospital, Boston MA, USA. (5) Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, USA. (6) Department of Medicine, Harvard Medical School, Boston MA, USA. Department of Medicine, Center for Head and Neck Cancers, Massachusetts General Hospital, Boston MA, USA. (7) Department of Medicine, Harvard Medical School, Boston MA, USA. Department of Medicine, Center for Head and Neck Cancers, Massachusetts General Hospital, Boston MA, USA. (8) Department of Medicine, Harvard Medical School, Boston MA, USA. Department of Medicine, Center for Head and Neck Cancers, Massachusetts General Hospital, Boston MA, USA. (9) Department of Medicine, Harvard Medical School, Boston MA, USA. Department of Medicine, Center for Head and Neck Cancers, Massachusetts General Hospital, Boston MA, USA. (10) Department of Medicine, Harvard Medical School, Boston MA, USA. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. (11) Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, USA. Department of Medicine, Harvard Medical School, Boston MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (12) Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, USA. Department of Medicine, Harvard Medical School, Boston MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Center for Engineering in Medicine and BioMEMS Resource Center, Surgical Services, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. (13) Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, USA. Department of Medicine, Harvard Medical School, Boston MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Medicine, Center for Head and Neck Cancers, Massachusetts General Hospital, Boston MA, USA.
Citation: Oncoimmunology 2025 Dec 14:2466308 Epub02/18/2025
