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Several clinical trials are ongoing to evaluate induction chemotherapy and immunotherapy for locally advanced head and neck squamous cell carcinoma (HNSCC) including oral cancer, with the aim of improving survival and functional outcomes. Our tumor-immune microenvironmental analyses based on multiplex immunohistochemistry and image cytometry revealed the presence of three types of immune characteristics, which were associated with the efficacy of induction chemotherapy in locally advanced HNSCC. Tissue biomarker-guided patient selection can optimize future treatment strategies including induction chemotherapy/immunotherapy and surgical procedures in oral cancer.

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Neutrophil-to-lymphocyte ratio (NLR) in peripheral blood is an emerging biomarker candidate of immunotherapy in a wide range of cancers. However, little is known about the potential relationships between the tumor immune microenvironment and systemic inflammatory markers including NLR. Here we have explored systemic and tumor-immune microenvironmental characteristics related to treatment outcomes of immune checkpoint inhibition, based on 29 consecutive patients with recurrent/metastatic head and neck squamous cell carcinoma who received pembrolizumab between 2020 and 2021. NLR greater than 4.5 at pretreatment status significantly correlated with short overall survival (OS). Although NLR did not show a significant association with tumor volumes, high NLR exhibited significant correlations with malnutrition status characterized by CONUT (controlling nutritional status), and GNRI (geriatric nutrition risk index). Among the patients whose NLR was greater than 4.5 at pretreatment status, those whose NLR decreased to less than 4.5 at day 21 had a better OS than those whose NLR did not decrease, indicating that longitudinal changes in NLR correlate with prognosis. To investigate association with tumor-immune microenvironment, 14-marker multiplex immunohistochemistry was performed to quantitatively evaluate intratumoral CD8+ T cells, helper T cells, regulatory T cells, B cells, natural killer cells, macrophages, dendritic cells, mast cells, and granulocytes. Notably, NLR at pretreatment status significantly correlated with intratumoral immune cell densities, where high NLR correlated with low lymphoid cells and high tumor associated macrophages in tissue. NLR in peripheral blood significantly correlated with myeloid to lymphoid cell ratios in tissue, suggesting the presence of association between circulating and intratumoral immune complexity profiles. This study highlights that the association between intratumoral myeloid predominance and systemic nutritional and inflammatory status might be a possible factor for resistance to immunotherapy. Understanding immune dynamics in tissue and blood during immunotherapy potentially contributes to the establishment of predictive biomarkers and monitoring for immunotherapy. Citation Format: Hiroki Morimoto, Takahiro Tsujikawa, Aya Miyagawa-Hayashino, Alisa Kimura, Sumiyo Saburi, Junichi Mitsuda, Kanako Yoshimura, Gaku Ohmura, Shigeyuki Mukudai, Hikaru Nagao, Yoichiro Sugiyama, Shibata Saya, Hiroshi Ogi, Eiichi Konishi, Kyoko Itoh, Shigeru Hirano. Neutrophil-to-lymphocyte ratio associates with intratumoral myeloid predominance and clinical outcomes of pembrolizumab in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4453.

Understanding longitudinal changes of tumor-immune microenvironment during chemo/targeted therapies contributes to the development of optimized combinations of immunotherapy with chemotherapy and targeted therapy for patients with head and neck squamous cell carcinoma (HNSCC). We previously reported a chromogenic sequential immunohistochemical (IHC) platform enabling quantitative and spatial assessment of 29+ biomarkers in a single tissue section (Tsujikawa T et al. Cell Reports 2017, Banik G et al. Methods Enzymology 2020). Using this platform, densities, phenotypes, and distributions of tumor and immune cells were evaluated, comparing baseline and post-treatment specimens from the same individual treated by paclitaxel, carboplatin, and cetuximab (PCE) for advanced HNSCC (N = 30). Immune cell density analyses based on CD8+ T cells, helper T cells, regulatory T cells, B cells, natural killer cells, macrophages, dendritic cells, mast cells, granulocytes revealed the presence of differential immune cell compositions, where immune profiles were divided into hypo-, lymphoid-, and myeloid-inflamed groups according to the same criteria as in our previous report (Tsujikawa et al. Cell Reports 2017). Lymphoid and hypo-inflamed groups exhibited significant tumor volume reduction, increased CD45+ immune cell densities and elevated combined positive scores of PD-L1 at the post-treatment status, suggesting the potential involvement of immunogenic mechanisms related to therapeutic response. On the other hand, the myeloid group exhibited no significant tumor volume reduction, together with higher expression of HIF1α and ZEB2 on tumor cells which are potentially associated with hypoxia and epithelial-mesenchymal transition. In conclusion, longitudinal tissue-based monitoring revealed the presence of differential tumor-immune complexity profiles related to therapeutic efficacy and resistance. Hypo-inflamed profiles might require upfront chemo/targeted therapy before immunotherapy, and myeloid-inflamed profiles might require myeloid cell-targeted therapies, mandating the establishment of rapid clinical assessment of tumor-immune microenvironment. Citation Format: Alisa Kimura, Takahiro Tsujikawa, Junichi Mitsuda, Aya Miyagawa-Hayashino, Hiroki Morimoto, Sumiyo Saburi, Kanako Yoshimura, Gaku Ohmura, Sigeyuki Mukudai, Hikaru Nagao, Yoichiro Sugiyama, Hiroshi Ogi, Saya Shibata, Eiichi Konishi, Kyoko Itoh, Shigeru Hirano. Tumor-immune microenvironmental profiling during chemo- and targeted therapy for head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5172.