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Stress Keratin 17 Is a Predictive Biomarker Inversely Associated with Response to Immune Check-Point Blockade in Head and Neck Squamous Cell Carcinomas and Beyond.

ABSTRACT: Low response rates in immune check-point blockade (ICB)-treated head and neck squamous cell carcinoma (HNSCC) drive a critical need for robust, clinically validated predictive biomarkers. Our group previously showed that stress keratin 17 (CK17) suppresses macrophage-mediated CXCL9/CXCL10 chemokine signaling involved in attracting activated CD8+ T cells into tumors, correlating with decreased response rate to pembrolizumab-based therapy in a pilot cohort of ICB-treated HNSCC (n = 26). Here, we performed an expanded analysis of the predictive value of CK17 in ICB-treated HNSCC according to the REMARK criteria and investigated the gene expression profiles associated with high CK17 expression. Pretreatment samples from pembrolizumab-treated HNSCC patients were stained via immunohistochemistry using a CK17 monoclonal antibody (n = 48) and subjected to spatial transcriptomic profiling (n = 8). Our findings were validated in an independent retrospective cohort (n = 22). CK17 RNA expression in pembrolizumab-treated patients with various cancer types was investigated for predictive significance. Of the 48 patients (60% male, median age of 61.5 years), 21 (44%) were CK17 high, and 27 (56%) were CK17 low. A total of 17 patients (35%, 77% CK17 low) had disease control, while 31 patients (65%, 45% CK17 low) had progressive disease. High CK17 expression was associated with a lack of disease control (p = 0.037), shorter time to treatment failure (p = 0.025), and progression-free survival (PFS, p = 0.004), but not overall survival (OS, p = 0.06). A high CK17 expression was associated with lack of disease control in an independent validation cohort (p = 0.011). PD-L1 expression did not correlate with CK17 expression or clinical outcome. CK17 RNA expression was predictive of PFS and OS in 552 pembrolizumab-treated cancer patients. Our findings indicate that high CK17 expression may predict resistance to ICB in HNSCC patients and beyond.

SUBMITTER: Lozar T

PROVIDER: S-EPMC10571921 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Stress Keratin 17 Is a Predictive Biomarker Inversely Associated with Response to Immune Check-Point Blockade in Head and Neck Squamous Cell Carcinomas and Beyond.

Lozar Taja T Laklouk Israa I Golfinos Athena E AE Gavrielatou Niki N Xu Jin J Flynn Christopher C Keske Aysenur A Yu Menggang M Bruce Justine Y JY Wang Wei W Grasic Kuhar Cvetka C Bailey Howard H HH Harari Paul M PM Dinh Huy Q HQ Rimm David L DL Hu Rong R Lambert Paul F PF Fitzpatrick Megan B MB

Cancers 20231009 19

Low response rates in immune check-point blockade (ICB)-treated head and neck squamous cell carcinoma (HNSCC) drive a critical need for robust, clinically validated predictive biomarkers. Our group previously showed that stress keratin 17 (CK17) suppresses macrophage-mediated CXCL9/CXCL10 chemokine signaling involved in attracting activated CD8+ T cells into tumors, correlating with decreased response rate to pembrolizumab-based therapy in a pilot cohort of ICB-treated HNSCC (<i>n</i> = 26). Her ...[more]

PMID: 37835599

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Project description:The success of immune checkpoint receptor blockade has brought exciting promises for the treatment of head and neck squamous cell carcinoma (HNSCC). While patients who respond to checkpoint inhibitors tend to develop a durable response, <15% of patients with HNSCC respond to immune checkpoint inhibitors, underscoring the critical need to alleviate cancer resistance to immunotherapy. Major advances have been made to elucidate the intrinsic and adaptive resistance mechanisms to immunotherapy. Central genomic events in HNSCC have been found to possess previously unknown roles in suppressing immune sensing. Such inhibitory function affects both the innate and adaptive arms of tumor-specific immunity. While checkpoint blockade effectively reinvigorates adaptive T-cell responses, additional targeting of the oncogenic inhibitors of innate immune sensing likely informs a novel and potent strategy for immune priming. This review discusses the recent advances on the identification of key HNSCC oncogenes that impair antitumor immunity and emerging immune-priming approaches that sensitize poorly immunogenic HNSCCs to checkpoint blockade. These approaches include but are not limited to cancer vaccine systems utilizing novel type I interferon agonists as immune adjuvants, radiation, DNA damage-inducing agents, and metabolic reprogramming. The goal of these multipronged approaches is to expand tumor-specific effector T-cells, break checkpoint receptor-mediated tolerance, and metabolically support sustained T-cell activation. The translation of therapeutics that reverses oncogenic inhibition of immune sensing requires thorough characterization of the HNSCC regulators of innate immune sensors, development of additional immunocompetent HNSCC mouse models, as well as engineering of more robust immune adjuvant delivery systems. Built on the success of checkpoint blockade, validation of novel immune-priming approaches holds key promises to expand the pool of responders to immunotherapy.

Project description:We previously identified stress keratin 17 (K17) as a host factor that contributes to immune evasion in the context of mouse papillomavirus-induced disease. Analyses of head and neck squamous cell carcinoma (HNSCC) patient TCGA and tissue microarray data revealed that K17 can be overexpressed in both HPV+ and HPV- human cancer samples, with a more profound upregulation in HPV- HNSCC samples. In this report, we investigated the role of K17 in regulating immune response in HPV- head and neck cancer. To test whether K17 mediates immune evasion and resistance to immune checkpoint blockade (ICB) therapy in HPV- HNC, we used MOC2, a K17-expressing murine HNC cell line, and knocked out the K17 gene from it using CRISPR/Cas9 (K17KO MOC2 cells). Then we injected K17KO MOC2 cells or parental MOC2 cells into NSG and C57BL/6 mice and monitored tumor growth, immune cell infiltration, and response to ICB treatment in vivo. In NSG mice, the K17KO MOC2 cell lines grew as fast as parental MOC2 tumors. In C57BL/6 mice, K17KO MOC2 tumors grew significantly slower than parental MOC2 tumors, with 50% tumor rejection rate, in a T-cell dependent manner. Flow cytometry of tumor infiltrating T cells and bulk tumor RNA seq analyses show an active anti-tumor microenvironment in the K17KO MOC2 tumors, compared to parental MOC2 tumors. In addition, we observed that 5 out of 5 anti-PD1 + anti-CTLA4 treated K17KO MOC2 tumors completely regressed, while only 1 out of 5 parental MOC2 tumors similarly treated at the same size completely regressed (p<0.05). In exploring the role of chemokine CXCL9 in increased T cell infiltration, we blocked the receptor CXCR3, a receptor often upregulated on activated T cells, and saw a delay in the immune-mediated rejection K17KO MOC2 tumors. Single cell RNA seq analyses revealed a completely different immune landscape including both lymphoid and myeloid populations in K17KO MOC2 tumors. Overall, we demonstrated that K17 expression in HNSCC contributes to immune evasion and resistance to immune checkpoint blockade treatment through modulating the immune landscape in the tumor microenvironment.

Dataset Information

Stress Keratin 17 Is a Predictive Biomarker Inversely Associated with Response to Immune Check-Point Blockade in Head and Neck Squamous Cell Carcinomas and Beyond.

Publications

Stress Keratin 17 Is a Predictive Biomarker Inversely Associated with Response to Immune Check-Point Blockade in Head and Neck Squamous Cell Carcinomas and Beyond.

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