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Background: The relationship between the tumor‐immune microenvironment and systemic inflammatory markers, including neutrophil‐to‐lymphocyte ratio (NLR), is unclear. Methods: We examined the characteristics of systemic inflammatory markers and tumor immune microenvironments in relation to treatment outcomes in 29 consecutive patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) who received pembrolizumab, using 14‐marker multiplex immunohistochemistry and image cytometry. Results: NLR ≥4.5 (high NLR) at pretreatment status significantly correlated with short overall survival (OS) and progression‐free survival‐2 (PFS2) and malnutrition status. High NLR in peripheral blood was significantly correlated with low lymphoid cell and high tumor‐associated macrophage counts in tissues, especially myeloid‐to‐lymphoid cell ratios, suggesting an association between circulating and intratumoral immune complexity profiles. Conclusions: This study suggests a link between NLR in circulating blood, systemic nutritional status, and immune composition within the tumor. [ABSTRACT FROM AUTHOR]

This document is the front cover of an article titled "Neutrophil-to-lymphocyte ratio associates with nutritional parameters, intratumoral immune profiles, and clinical outcomes of pembrolizumab in head and neck squamous cell carcinoma" by Hiroki Morimoto et al. The article explores the relationship between the neutrophil-to-lymphocyte ratio and various factors such as nutritional parameters, immune profiles, and clinical outcomes in patients with head and neck squamous cell carcinoma who received pembrolizumab treatment. The authors of the article are Hiroki Morimoto, Takahiro Tsujikawa, Aya Miyagawa-Hayashino, Alisa Kimura, Sumiyo Saburi, Nanako Murakami, Kayo Kitamoto, Shigeyuki Mukudai, Hikaru Nagao, Shibata Saya, Hiroshi Ogi, Eiichi Konishi, Kyoko Itoh, and Shigeru Hirano. [Extracted from the article]

Background: Functional interactions between immune cells and neoplastic cells in the tumor immune microenvironment have been actively pursued for both biomarker discovery for patient stratification, as well as therapeutic anti-cancer targets to improve clinical outcomes. Although accumulating evidence indicates that intratumoral infiltration of immune cells has prognostic significance, limited information is available on the spatial infiltration patterns of immune cells within intratumoral regions. This study aimed to understand the intratumoral heterogeneity and spatial distribution of immune cell infiltrates associated with cell phenotypes and prognosis in head and neck squamous cell carcinoma (HNSCC). Methods: A total of 88 specimens of oropharyngeal squamous cell carcinoma, categorized into discovery (n = 38) and validation cohorts (n = 51), were analyzed for immune contexture by multiplexed immunohistochemistry (IHC) and image cytometry-based quantification. Tissue segmentation was performed according to a mathematical morphological approach using neoplastic cell IHC images to dissect intratumoral regions into tumor cell nests versus intratumoral stroma. Results: Tissue segmentation revealed heterogeneity in intratumoral T cells, varying from tumor cell nest-polarized to intratumoral stroma-polarized distributions. Leukocyte composition analysis revealed higher ratios of TH1/TH2 in tumor cell nests with higher percentages of helper T cells, B cells, and CD66b+ granulocytes within intratumoral stroma. A discovery and validation approach revealed a high density of programmed death receptor-1 (PD-1)+ helper T cells in tumor cell nests as a negative prognostic factor for short overall survival. CD163+ tumor-associated macrophages (TAM) provided the strongest correlation with PD-1+ helper T cells, and cases with a high density of PD-1+ helper T cells and CD163+ TAM had a significantly shorter overall survival than other cases. Conclusion: This study reveals the significance of analyzing intratumoral cell nests and reports that an immune microenvironment with a high density of PD-1+ helper T cells in tumoral cell nests is a poor prognostic factor for HNSCC. [ABSTRACT FROM AUTHOR]

Background: In view of improving biomarkers predicting the efficacy of immunotherapy for head and neck squamous cell carcinoma (R/M HNSCC), this multicenter retrospective study aimed to identify clinical, tumor microenvironmental, and genomic factors that are related to therapeutic response to the anti- Programmed cell death protein 1 (PD-1) antibody, nivolumab, in patients with R/M HNSCC., Methods: The study compared 53 responders and 47 non-responders, analyzing formalin-fixed paraffin-embedded samples using 14-marker multiplex immunohistochemistry and targeted gene sequencing., Results: Of 100 patients included, responders had significantly lower smoking and alcohol index, higher incidence of immune related adverse events, and higher PD-1 ligand (PD-L1) expression in immune cells as well as PD-L1 combined positive score (CPS) than non-responders. The frequency of natural killer cells was associated with nivolumab response in patients with prior cetuximab use, but not in cetuximab-naïve status. Age-stratified analysis showed nivolumab response was linked to high CPS and lymphoid-inflamed profiles in patients aged ≥ 65. In contrast, lower NLR in peripheral blood counts was associated with response in patients aged < 65. Notably, TP53 mutation-positive group had lower CPS and T cell densities, suggesting an immune-excluded microenvironment. Patients with altered tumor suppressor gene pathways, including TP53 , CDKN2A , and SMAD4 mutations, had lower CPS, higher smoking index, and were associated with poor responses., Conclusion: Nivolumab treatment efficacy in HNSCC is influenced by a combination of clinical factors, age, prior treatment, immune environmental characteristics, and gene mutation profiles., Competing Interests: TT received lecture honoraria, consulting fees, and grants from Ono Pharmaceutical Co., Ltd. and lecture honoraria from Bristol Myers Squibb, and Merck Sharp & Dohme Corp. KO received grants from Ono Pharmaceutical Co., Ltd. HO and SS were employed by SCREEN Holdings Co., Ltd. YaS received lecture honoraria from Bristol Myers Squibb, Merck Sharp & Dohme Corp, and Ono Pharmaceutical Co., Ltd. RH received lecture honoraria from Rakuten Medical Inc. YuS received grants from Merck Sharp & Dohme Corp. KT received lecture honoraria from Bristol Myers Squibb, Merck Sharp & Dohme Corp, and Ono Pharmaceutical Co., Ltd. NO received lecture honoraria and grants from Ono Pharmaceutical Co., Ltd and lecture honoraria from Bristol-Myers Squibb. NH received lecture honoraria from Bristol Myers Squibb, and Ono Pharmaceutical Co., Ltd. KN received lecture honoraria from Merck Sharp & Dohme Corp, and Ono Pharmaceutical Co., Ltd. SI received lecture honoraria and grants from Ono Pharmaceutical Co., Ltd and lecture honoraria from Bristol Myers Squibb. KI received grants from SCREEN Holdings Co., Ltd. TAs received grants from Ono Pharmaceutical Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Tsujikawa, Ohno, Morita, Saburi, Mitsuda, Yoshimura, Kimura, Morimoto, Ogi, Shibata, Akashi, Kurata, Imoto, Shimizu, Kano, Watanabe, Yamazaki, Asada, Hayashi, Saito, Ozawa, Tsukahara, Oridate, Sano, Horii, Ueki, Maruo, Mukoyama, Hanai, Fukusumi, Iwai, Fujisawa, Fujii, Nibu, Iwae, Ueda, Chikuie, Yasumatsu, Matsuo, Umeno, Ono, Masuda, Toh, Itoh, Hirano and Asakage.)

Background: Functional interactions between immune cells and neoplastic cells in the tumor immune microenvironment have been actively pursued for both biomarker discovery for patient stratification, as well as therapeutic anti-cancer targets to improve clinical outcomes. Although accumulating evidence indicates that intratumoral infiltration of immune cells has prognostic significance, limited information is available on the spatial infiltration patterns of immune cells within intratumoral regions. This study aimed to understand the intratumoral heterogeneity and spatial distribution of immune cell infiltrates associated with cell phenotypes and prognosis in head and neck squamous cell carcinoma (HNSCC)., Methods: A total of 88 specimens of oropharyngeal squamous cell carcinoma, categorized into discovery (n = 38) and validation cohorts (n = 51), were analyzed for immune contexture by multiplexed immunohistochemistry (IHC) and image cytometry-based quantification. Tissue segmentation was performed according to a mathematical morphological approach using neoplastic cell IHC images to dissect intratumoral regions into tumor cell nests versus intratumoral stroma., Results: Tissue segmentation revealed heterogeneity in intratumoral T cells, varying from tumor cell nest-polarized to intratumoral stroma-polarized distributions. Leukocyte composition analysis revealed higher ratios of T H 1/T H 2 in tumor cell nests with higher percentages of helper T cells, B cells, and CD66b + granulocytes within intratumoral stroma. A discovery and validation approach revealed a high density of programmed death receptor-1 (PD-1) + helper T cells in tumor cell nests as a negative prognostic factor for short overall survival. CD163 + tumor-associated macrophages (TAM) provided the strongest correlation with PD-1 + helper T cells, and cases with a high density of PD-1 + helper T cells and CD163 + TAM had a significantly shorter overall survival than other cases., Conclusion: This study reveals the significance of analyzing intratumoral cell nests and reports that an immune microenvironment with a high density of PD-1 + helper T cells in tumoral cell nests is a poor prognostic factor for HNSCC., Competing Interests: TT is a paid consultant for Ono Pharmaceutical and receives speaker fees from Merck Sharp & Dohme Corp, Ono Pharmaceutical, and Bristol-Myers Squibb. HO is an employee of SCREEN Holdings Co., Ltd. SSh is an employee of SCREEN Holdings Co., Ltd. EK is a paid consultant for Roche Diagnostics and receives speaker fees from Chugai Pharmaceutical. KI received research funding from the SCREEN Holdings Co., Ltd. LC is a paid consultant for Cell Signaling Technologies, AbbVie Inc., and Shasqi Inc., received reagent and/or research support from Plexxikon Inc., Pharmacyclics, Inc., Acerta Pharma, LLC, Deciphera Pharmaceuticals, LLC, Genentech, Inc., Roche Glycart AG, Syndax Pharmaceuticals Inc., Innate Pharma, NanoString Technologies, and Cell Signaling Technologies, is a member of the Scientific Advisory Boards of Syndax Pharmaceuticals, Carisma Therapeutics, Zymeworks, Inc, Verseau Therapeutics, Cytomix Therapeutics, Inc., Hibercell, Inc., Alkermes, Inc., Genenta Sciences, and Kineta Inc, and is a member of the Lustgarten Therapeutics Advisory working group, and the AstraZeneca Partner of Choice Network. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yoshimura, Tsujikawa, Mitsuda, Ogi, Saburi, Ohmura, Arai, Shibata, Thibault, Chang, Clayburgh, Yasukawa, Miyagawa-Hayashino, Konishi, Itoh, Coussens and Hirano.)