The immune phenotype of tongue squamous cell carcinoma predicts early relapse and poor prognosis

Troiano, Giuseppe; Rubini, Corrado; Togni, Lucrezia; Caponio, Vito Carlo Alberto; Zhurakivska, Khrystyna; Santarelli, Andrea; Cirillo, Nicola; Muzio, Lorenzo Lo; Mascitti, Marco

doi:10.1002/cam4.3440

Cited by 50 publications

(53 citation statements)

References 56 publications

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“…We predicted that not only the clonal expansion of TIL but, also, PD-L1 suppression, which is likely upregulated during chemotherapy and chemoradiation therapy, should play an important role in improving the prognosis. This viewpoint was supported by previous results in other types of cancers, such as extrahepatic bile duct cancers, non-small cell lung carcinoma, or tongue squamous cell carcinoma [ 18 , 21 , 22 , 36 , 37 ]. However, the results presented here should be validated by another clinical cohort because of the limited number of enrolled patients, especially for the prognostic study of salvage surgery after definitive CRT, and also validated by using endoscopic biopsies before salvage surgeries to establish the predictive markers.…”

Section: Discussionsupporting

confidence: 85%

“…These results prompted us to hypothesize that the clonal expansion of TIL, which occurred in all the cases after definitive CRT examined in this study, might not be enough and should be followed or accompanied by PD-L1 suppression, although the upregulation of PD-L1 is likely to be induced after neoadjuvant chemotherapy, as previously reported [ 33 ]. This hypothesis is plausible, because similar results have been reported in various human cancers; the lack of PD-L1 expression and the combined presence of CD8+ TIL were associated with favorable survival rates in stage III non-small cell lung carcinoma after CRT, as well as in patients with extrahepatic bile duct cancer after surgery and adjuvant chemoradiation therapy [ 18 , 22 , 36 ]; the immunophenotypes determined by TIL density and their spatial organization in the tumor, which might be influenced by the infiltration of CD8+ TIL and expression of PD-L1 or PD-1, were reportedly prognostic marker candidates of tongue squamous cell carcinoma [ 37 ]. The salvage surgery for ESCC that locally relapses after definitive CRT is surgically feasible; however, severe comorbidities such as pneumonia or anastomotic leakage are often reported [ 7 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

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Clonal Expansion of Tumor-Infiltrating T Cells and Analysis of the Tumor Microenvironment within Esophageal Squamous Cell Carcinoma Relapsed after Definitive Chemoradiation Therapy

Mori

Kumagai

Nasu

et al. 2021

IJMS

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(1) Background: Comparable prognoses after definitive chemoradiation therapy (CRT) to surgery alone for esophageal squamous cell carcinoma (ESCC) have been previously reported; however, no robust prognostic markers have been established. The clonality of tumor-infiltrating lymphocytes (TILs) and tumor microenvironments (TMEs) in ESCC relapsed after CRT were examined to explore prognostic markers. (2) Methods: Clonality of TIL and TME were examined in ESCC with and without preceding CRT, as well as oral squamous cell carcinoma (OSCC) and healthy volunteers as controls. The clonality of TIL was assessed by T-cell receptor (TCR) α and β repertoire analyses and evaluated by diversity indices. The TME was assessed by quantitative polymerase chain reaction evaluating PD-L1 and CD8B. (3) Results: The clonal expansion of TIL was significantly induced within ESCCs and OSCCs, when compared to healthy volunteers, and was mostly induced within ESCCs after definitive CRT. Diversity indices of TIL were not associated with the prognosis, but the ratio of PD-L1 mRNA to CD8B mRNA in TME was significantly associated with a poor prognosis after salvage surgery (p = 0.007). (4) Conclusions: The clonal expansion of TIL is induced after definitive CRT for ESCC, and the ratio of PD-L1 mRNA to CD8B mRNA within tumor tissues is a prognostic marker candidate for salvage esophagectomy after CRT.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Clonal Expansion of Tumor-Infiltrating T Cells and Analysis of the Tumor Microenvironment within Esophageal Squamous Cell Carcinoma Relapsed after Definitive Chemoradiation Therapy

Mori

Kumagai

Nasu

et al. 2021

IJMS

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“…Tumor-infiltrating CD8 + T lymphocytes can also be aberrantly active and immunologically exhausted. In a recent study, Troiano et al identified a specific subgroup of squamous cell carcinoma of the oral tongue with poor prognosis based on the density of tumor‐infiltrating lymphocytes and localization ( 71 ). Thus, the tumor immune phenotyping can be a better approach to stratify patients and decide on precision medicine.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of Complement Properdin in Cancer

Mangogna

Varghese²,

Agostinis³

et al. 2021

Front. Immunol.

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The complement system is readily triggered by the presence of damage-associated molecular patterns on the surface of tumor cells. The complement alternative pathway provides rapid amplification of the molecular stress signal, leading to complement cascade activation to deal with pathogens or malignant cells. Properdin is the only known positive regulator of the alternative pathway. In addition, properdin promotes the phagocytic uptake of apoptotic T cells by macrophages and dendritic cells without activating the complement system, thus, establishing its ability to recognize “altered-self”. Dysregulation of properdin has been implicated in substantial tissue damage in the host, and in some cases, chronic unresolved inflammation. A corollary of this may be the development of cancer. Hence, to establish a correlation between properdin presence/levels in normal and cancer tissues, we performed bioinformatics analysis, using Oncomine and UALCAN. Survival analyses were performed using UALCAN and PROGgeneV2 to assess if properdin can serve as a potential prognostic marker for human lung adenocarcinoma (LUAD), liver hepatocellular carcinoma (LIHC), cervical squamous cell carcinoma (CESC), and pancreatic adenocarcinoma (PAAD). We also analyzed levels of tumor-infiltrating immune cells using TIMER, a tool for characterizing immune cell composition in cancers. We found that in LUAD and LIHC, there was a lower expression of properdin in the tumors compared to normal tissues, while no significant difference was observed in CESC and PAAD. Survival analysis demonstrated a positive association between properdin mRNA expression and overall survival in all 4 types of cancers. TIMER analysis revealed that properdin expression correlated negatively with tumor purity and positively with levels of infiltrating B cells, cytotoxic CD8+ T cells, CD4+ helper T cells, macrophages, neutrophils and dendritic cells in LUAD, CESC and PAAD, and with levels of B cells, CD8+ T cells and dendritic cells in LIHC. Immunohistochemical analysis revealed that infiltrating immune cells were the most likely source of properdin in the tumor microenvironment. Thus, complement protein properdin shows promise as a prognostic marker in cancer and warrants further study.

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“…classified tongue carcinomas into immune-inflamed (when lymphocytes were found next to tumor cells), immune-excluded (when lymphocytes were found in the stroma, outside the tumor), or immune-desert (absence of lymphocytes). Immune desert was the less frequent subgroup, but exhibited worse overall survival ( 39 ).…”

Section: The Immune Landscape Of Head and Neck Squamous Cell Carcinommentioning

confidence: 99%

Overcoming Resistance to Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinomas

2021

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Preclinical data suggest that head and neck squamous cell carcinomas (HNSCC) may evade immune surveillance and induce immunosuppression. One mechanism of immune evasion involves the expression of programmed death ligand-1 (PD-L1) in tumor and immune cells, which is, to date, the only biomarker routinely used in clinical practice to select patients with advanced HNSCCs more likely to benefit from anti-PD-1 therapy. Nonetheless, PD-L1 expression alone incompletely captures the degree of sensitivity of HNSCCs to PD-1 inhibitors. Most patients exposed to anti-PD-1 antibodies do not respond to therapy, suggesting the existence of mechanisms of de novo resistance to immunotherapy. Furthermore, patients that initially respond to PD-1 inhibitors will eventually develop acquired resistance to immunotherapy through mechanisms that have not yet been completely elucidated. In this article, we will provide an overview of the immune landscape of HNSCCs. We will briefly describe the clinical activity of inhibitors of the PD-1/PD-L1 axis in this disease, as well as biomarkers of benefit from these agents that have been identified so far. We will review pre-clinical and clinical work in cancers in general, and in HNSCCs specifically, that have characterized the mechanisms of de novo and acquired resistance to immunotherapy. Lastly, we will provide insights into novel strategies under investigation to overcome resistance to immune checkpoint inhibitors.

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The immune phenotype of tongue squamous cell carcinoma predicts early relapse and poor prognosis

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 50 publications

References 56 publications

Clonal Expansion of Tumor-Infiltrating T Cells and Analysis of the Tumor Microenvironment within Esophageal Squamous Cell Carcinoma Relapsed after Definitive Chemoradiation Therapy

Clonal Expansion of Tumor-Infiltrating T Cells and Analysis of the Tumor Microenvironment within Esophageal Squamous Cell Carcinoma Relapsed after Definitive Chemoradiation Therapy

Prognostic Value of Complement Properdin in Cancer

Overcoming Resistance to Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinomas

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