Preexisting tumor-resident T cells with cytotoxic potential associate with response to neoadjuvant anti-PD-1 in head and neck cancer

Giacomo Oliveira, Ann Marie Egloff, Alexander B. Afeyan, Jacquelyn O. Wolff, Zexiang Zeng, Rebecca D. Chernock, Liye Zhou, Cameron Messier, Patrick Lizotte, Kathleen L. Pfaff, Kari Stromhaug, Livius Penter, Robert I. Haddad, Glenn J. Hanna, Jonathan D. Schoenfeld, Laura A. Goguen, Donald J. Annino, Vickie Jo, Peter Oppelt, Patrik PipkornRyan Jackson, Sidharth V. Puram, Randal C. Paniello, Jason T. Rich, Jason Webb, Jose P. Zevallos, Mena Mansour, Jingxin Fu, Gavin P. Dunn, Scott J. Rodig, Jessica Ley, Luc G.T. Morris, Lara Dunn, Cloud P. Paweletz, Dorina Kallogjeri, Jay F. Piccirillo, Douglas R. Adkins, Catherine J. Wu, Ravindra Uppaluri

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13 Scopus citations


About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration of anti-programmed cell death protein 1 (PD-1) immunotherapy results in substantial pathologic tumor responses (pTR) within the tumor microenvironment (TME). However, the mechanisms underlying the dynamics of antitumor T cells upon neoadjuvant PD-1 blockade remain unresolved, and approaches to increase pathologic responses are lacking. In a phase 2 trial (NCT02296684), we observed that 45% of patients treated with two doses of neoadjuvant pembrolizumab experienced marked pTRs (≥50%). Single-cell analysis of 17,158 CD8+ T cells from 14 tumor biopsies, including 6 matched pre-post neoadjuvant treatment, revealed that responding tumors had clonally expanded putative tumor-specific exhausted CD8+ tumor-infiltrating lymphocytes (TILs) with a tissue-resident memory program, characterized by high cytotoxic potential (CTX+) and ZNF683 expression, within the baseline TME. Pathologic responses after 5 weeks of PD-1 blockade were consistent with activation of preexisting CTX+ZNF683+CD8+ TILs, paralleling loss of viable tumor and associated tumor antigens. Response was associated with high numbers of CD103+PD-1+CD8+ T cells infiltrating pretreatment lesions, whereas revival of nonexhausted persisting clones and clonal replacement were modest. By contrast, nonresponder baseline TME exhibited a relative absence of ZNF683+CTX+ TILs and subsequent accumulation of highly exhausted clones. In HNSCC, revival of preexisting ZNF683+CTX+ TILs is a major mechanism of response in the immediate postneoadjuvant setting.

Original languageEnglish
Article numbereadf4968
JournalScience immunology
Issue number87
StatePublished - Sep 2023


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