With the recent success of checkpoint inhibitors and other immune-modulating agents, there has been renewed interest in the combination of such agents with radiation. The biological premise behind such a strategy is that the tumor-antigen release achieved by localized radiation will promote specific tumor-targeting by the adaptive immune system, which can be augmented further by systemic immune-stimulating agents. In this manner, clinicians hope to induce a phenomenon known as the abscopal effect, whereby localized radiation results in immune-mediated tumor regression in disease sites well outside of the radiation field. In this Crossroads in Cancer Immunology article, we will present a comprehensive overview of the early clinical and pre-clinical evidence behind this approach.
Immune checkpoint therapies exhibit impressive efficacy in some patients with melanoma or lung cancer, but the lack of response in most cases presses the question of how general efficacy can be improved. In addressing this question, we generated a preclinical tumor model to study anti-PD-1 resistance by in vivo passaging of Kras-mutated, p53-deficient murine lung cancer cells (p53R172HΔg/+K-rasLA1/+) in a syngeneic host exposed to repetitive dosing with anti-mouse PD-1 antibodies. PDL1 (CD274) expression did not differ between the resistant and parental tumor cells. However the expression of important molecules in the antigen presentation pathway, including major histocompatibility complex (MHC) class I and II, as well as β2-microglobulin were significantly downregulated in the anti-PD1-resistant tumors compared with parental tumors. Resistant tumors also contained fewer CD8+ (CD8α) and CD4+ tumor-infiltrating lymphocytes (TILs) and reduced production of interferon-γ (IFN-γ). Localized radiotherapy induced IFN-β production, thereby elevating MHC class I expression on both parental and resistant tumor cells and restoring the responsiveness of resistant tumors to anti-PD1 therapy. Conversely, blockade of type I IFN signaling abolished the effect of radiosensitization in this setting. Collectively, these results identify a mechanism of PD1 resistance and demonstrate that adjuvant radiation therapy can overcome resistance. These findings have immediate clinical implications for extending the efficacy of anti-PD-1 immune checkpoint therapy in patients.
Fascin-1 and E-cadherin, both of which are related to cell motility and cell adhesiveness, are important factors in the progression and metastasis of cancers. The objective of this study was to explore the association between fascin-1 and E-cadherin expression levels with both the clinical characteristics and prognoses of patients with laryngeal squamous cell carcinoma; we did so through statistical analyses. In our study, tumor tissue samples from 150 patients with laryngeal squamous cell carcinoma were examined for fascin-1 and E-cadherin expression by immunohistochemistry. Fascin-1 expression was found to be an independent predictive factor for recurrence in patients with laryngeal squamous cell carcinoma (P = 0.021) and independently related to disease-free survival (P = 0.010). Although E-cadherin expression status was not an independent predictive factor for recurrence (P = 0.055) or disease-free survival (P = 0.063), when using subgroup analysis, the subgroup with high fascin-1 expression/low E-cadherin expression had the poorest prognosis (P = 0.000). Fascin-1 expression could be a potential prognostic predictor for patients with laryngeal squamous cell carcinoma. Simultaneous analyses of fascin-1 and E-cadherin expression could be more effective in evaluating the prognoses of patients with laryngeal squamous cell carcinoma.
Immunohistochemical assessment of both Survivin and CD44v6 status in negative surgical margin may be a valuable approach for predicting recurrence and survival after curative surgery for laryngeal cancer.
We presented our experiences in treatment of Cerebrospinal Fluid (CSF) rhinorrhea with an endoscopic endonasal surgery approach, and showed the severe postoperative complications and failures we experienced, in order to outline some of the characteristic problems that can occur. We performed a retrospective analysis of all of the patients with CSF rhinorrhea. All of the patients were managed with an endonasal endoscopic procedure. Data collected included the site of leakage, the surgical interventions, and the postoperative complications. Sixty-nine patients (33 females and 36 males) were included in this study. All patients underwent an endoscopic repair approach with a multilayer reconstructive technique. The success rates of the first attempt in our study were 89%. Four patients presented with postoperative meningitis and brain abscess and one of these patients died of the brain abscess. Our results indicate that an endoscopic endonasal surgery approach provides a wide, safe, and direct route for treatment of CSF rhinorrhea. The precise location of leakage prior to surgery and proper patient selection, eliminating those with large leakages, are helpful in ensuring a successful endoscopic CSF repair with minimal mortality.
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