Preexisting tumor-resident T cells with cytotoxic potential associate with response to neoadjuvant anti-PD-1 in head and neck cancer Journal Article
| Authors: | Oliveira, G.; Egloff, A. M.; Afeyan, A. B.; Wolff, J. O.; Zeng, Z.; Chernock, R. D.; Zhou, L.; Messier, C.; Lizotte, P.; Pfaff, K. L.; Stromhaug, K.; Penter, L.; Haddad, R. I.; Hanna, G. J.; Schoenfeld, J. D.; Goguen, L. A.; Annino, D. J.; Jo, V.; Oppelt, P.; Pipkorn, P.; Jackson, R.; Puram, S. V.; Paniello, R. C.; Rich, J. T.; Webb, J.; Zevallos, J. P.; Mansour, M.; Fu, J.; Dunn, G. P.; Rodig, S. J.; Ley, J.; Morris, L. G. T.; Dunn, L.; Paweletz, C. P.; Kallogjeri, D.; Piccirillo, J. F.; Adkins, D. R.; Wu, C. J.; Uppaluri, R. |
| Article Title: | 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. |
| Keywords: | antineoplastic agents; neoadjuvant therapy; antineoplastic agent; cd8+ t lymphocyte; cd8-positive t-lymphocytes; head and neck neoplasms; head and neck tumor; head and neck squamous cell carcinoma; tumor microenvironment; humans; human; squamous cell carcinoma of head and neck |
| Journal Title: | Science Immunology |
| Volume: | 8 |
| Issue: | 87 |
| ISSN: | 2470-9468 |
| Publisher: | Amer Assoc Advancement Science |
| Date Published: | 2023-09-01 |
| Start Page: | eadf4968 |
| Language: | English |
| DOI: | 10.1126/sciimmunol.adf4968 |
| PUBMED: | 37683037 |
| PROVIDER: | scopus |
| PMCID: | PMC10794154 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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