Stem cell-like T cell depletion in the recurrent head and neck cancer immune microenvironment

ABSTRACT

Human papilloma virus (HPV)-related oncogenesis in head and neck cancer establishes a local microenvironment rich with immune cells, however the composition of the microenvironment in recurrent disease following definitive treatment is poorly understood. Here, we investigate the composition and spatial relationships between tumor and immune cells in recurrent head and neck cancer following curative intent chemoradiotherapy. Multiplexed immunofluorescence with 12 unique markers, through two multiplex immunofluorescent panels, was performed to evaluate 27 tumor samples including 18 pre-treatment primary and 9 paired recurrent tumors. Tumor and immune cell populations were phenotyped and quantified using a previously validated semi-automated digital pathology platform for cell segmentation. Spatial analysis was conducted by evaluating immune cells within the tumor, peri-tumoral stroma, and distant stroma. Initial tumors in patients with subsequent recurrence were found to be enriched in tumor associated macrophages and displayed an immune excluded spatial distribution. Recurrent tumors after chemoradiation were hypo-inflamed, with a statistically significant reduction in the recently identified stem-like TCF1+ CD8 T-cells, which normally function to maintain HPV-specific immune responses in the setting of chronic antigen exposure. Our findings indicate that the tumor microenvironment of recurrent HPV-related head and neck cancers displays a reduction in stem-like T cells, consistent with an immune microenvironment with a reduced ability to mount T-cell-driven anti-tumor immune responses.

Keywords:

• TCF1+ T-cell
• HPV
• head and neck cancer
• tumor immune microenvironment
• recurrent
• chemoradiation

Acknowledgments

This work was funded and/or supported by the Imaging and Radiation Science (IMRAS) program at MSKCC, the Jamie and Judith Dimon Center for HPV-related malignancies, and the National Institutes of Health (NIH)/National Cancer Institute Cancer Center Support Grant P30 CA008 and by the Parker Institute for Cancer Immunotherapy. J. S. Reis-Filho is funded in part by the NIH/NCI P50 CA247749 01, a Breast Cancer Research Foundation grant and a Susan G. Komen leadership grant.

Disclosure statement

J.S. Reis-Filho reports receiving personal/consultancy fees from Goldman Sachs, REPARE Therapeutics, Paige.AI, Personalis, and Eli Lilly, membership of the scientific advisory boards of VolitionRx, REPARE Therapeutics, Paige.AI and Personalis, membership of the Board of Directors of Grupo Oncoclinicas, and ad hoc membership of the scientific advisory boards of Roche Tissue Diagnostics, Ventana Medical Systems, Novartis, Genentech, MSD, Daiichi Sankyo, and InVicro, outside the scope of this study. N.L. reports receiving consultancy fees from Merck, Merck EMD, Elsie, and Mirati, outside the scope of this study. E.S. reports personal fees from Regeneron, Eli Lilly, and Roche, outside the scope of this study. T.H. receives research funding from Bristol Meyers Squibb, and Calico laboratories, outside the scope of this study. L.M. is listed on intellectual property owned by MSKCC and licensed to PDGX, outside the scope of this study. N.R. receives research support from Bristol Meyers Squibb, Pfizer, Repare, and Repertoire, that is outside the scope of this study.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2230666

Additional information

Funding

The work was supported by the Jamie and Judith Dimon Center for HPV-related malignancies Imaging and Radiation Science (IMRAS) program at MSKCC National Institutes of Health (NIH)/National Cancer Institute Cancer Center Support Grant [P30 CA008].