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

Abstract

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.

Abstract

Neoadjuvant anti–PD-1 HNSCC response associates with revival of preexisting TILs with cytotoxic potential and resident memory program.

Editor’s summary

Immune checkpoint blockade (ICB) such as anti-PD-1 reinvigorates tumor-specific T cell responses, but the mechanisms underlying specific clinical responses remain unclear. Using single-cell transcriptomics and TCR sequencing, Oliveira et al . analyzed tumor specimens from patients with head and neck cancer enrolled in a phase II clinical trial testing two doses of neoadjuvant anti–PD-1 before surgical resection. Tumors responding to anti–PD-1 contained a baseline population of ZNF683 ⁺ CD8 ⁺ T cells expressing genes associated with T cell exhaustion, tissue resident memory, and cytotoxicity. In paired pre- and post-treatment biopsies, ZNF683 ⁺ CD8 ⁺ T cells were clonally expanded and exhibited the strongest change in patients responding to ICB. These findings identify reinvigoration of cytotoxicity among ZNF683 ⁺ CD8 ⁺ T cells as a likely mechanism underlying response to neoadjuvant anti–PD-1 in head and neck cancer. —Claire Olingy