Allergen-specific sublingual immunotherapy (SLIT) is a potentially effective disease-modification treatment for patients with allergic asthma. Because CD44 signaling enhances regulatory T (Treg) cell-induction, administering CD44 ligands such as hyaluronan (HA) with allergen-specific SLIT may enhance the therapeutic effects. We evaluated the role of CD44 in Treg cell-induction in T helper type 2 (Th2)-mediated chronic airway inflammation using CD44 -/- mice and the efficacy of HA on SLIT in a Dermatophagoides farinae (Df)-induced murine model of chronic asthma. Th2 responses and Treg cell induction were evaluated in CD44 -/- mice. We devised a new SLIT model of Df-induced chronic asthma utilizing HA as an adjuvant. The effects of HA added to the new SLIT model were evaluated by the early asthmatic response (EAR) and airway hyperresponsiveness (AHR), eosinophilic airway inflammation, and serum Df-specific IgE levels. Th2-mediated chronic eosinophilic airway inflammation was worse in CD44 -/- mice compared with Df-sensitized wild-type (WT) mice. HA enhanced the effect of Df-induced Treg cells in a CD44-dependent manner. Sublingual Df treatment in combination with HA, but not alone, normalized EAR and AHR, and significantly reduced the serum IgE levels and the BALF eosinophil number. HA also induced Treg cells in a Df-sensitized spleen cell culture in a CD44-dependent manner. The treatment enhancing effects of HA in this SLIT model were diminished in CD44 -/- mice. CD44 is a key contributor to Treg cell induction and critical for the enhancing effects of HA in a Df-induced murine model of chronic asthma.

Introduction: Immunotherapy with immune checkpoint inhibitors (ICI) is the standard of care for advanced non-small-cell lung cancer (NSCLC) without driver gene alterations. However, survival benefits with ICI are limited to a small subset of NSCLC patients, and particularly ICI combinations with cytotoxic agents produce serious physical and large financial toxicities. Tumor PD-L1 expression levels/proportion score (TPS) are universally used as predictive biomarkers in ICI monotherapy response and outcomes. However, PD-L1/TPS assays are imperfect because of low analytical validity and reproducibility due to the visual-scoring system by pathologists. Therefore, additional biomarkers are urgently needed to predict ICI therapy response and outcomes. Recently, we reported that serum antibodies (Abs) against NY-ESO-1 and XAGE1 cancer-testis antigens were probably useful biomarkers in the prediction of clinical benefits with anti-PD-1 monotherapy for NSCLC (J Thorac Oncol, 2019). Additionally, we developed a fully automated immunoassay system (HISCLTM) to measure the Abs easily and rapidly (Sakai Y, et al. Clin Chim Acta 2021). In this study, we retrospectively examined whether the Abs measured by HISCLTM predict the clinical benefits with ICI monotherapy for NSCLC.Patients and Methods: Sera were obtained from controls of non-malignant lung diseases (n=75) and healthy subjects (n=100), and advanced NSCLC patients (n=263) to to determine a cutoff value in HISCLTM. In NSCLC patients analyzed here (n=78), sera were obtained before anti-PD-1 monotherapy with nivolumab in second-line or later settings. The serum NY-ESO-1/XAGE1 Abs were measured by HISCLTM, and we examined the relationships between the Abs levels, objective response rate (ORR), progression free survival (PFS), and overall survival (OS) after nivolumab monotherapy.Results: NY-ESO-1/XAGE1 Abs levels in NSCLC patients (n=263) were significantly higher than those in the controls (n=175). A cutoff value was determined as the Abs level of 10 SU/mL, calculated from the Abs values in the controls. The Abs (≥ 10 SU/mL) were detected in 21/78 (27%) of the NSCLC patients treated with nivolumab, and one patient had both NY-ESO-1 and XAGE1 Ab. An ORR was 62%, 16%, and 29% in the Abs-positives, the Abs-negatives, and overall, respectively. The Abs levels in responders were significantly higher than those in non-responders. The NSCLC patients with high-Abs values (≥ 10 SU/mL) had significantly better survivals with nivolumab monotherapy than those with low-Abs (PFS, HR 0.51, 95%CI 0.31-0.83, p < 0.01; OS, HR 0.51, 95%CI 0.31-0.84, p < 0.01). Interestingly, a few NSCLC patients with both high-Abs and driver genes responded well to nivolumab.Conclusions: Serum NY-ESO-1/XAGE1 Abs measured by HISCLTM are potential biomarkers that predict clinical benefits with anti-PD-1 monotherapy for NSCLC, even including driver genes. These findings warrant further biomarker studies using NY-ESO-1/XAGE1 Abs in clinical trial and practice of NSCLC immunotherapy. Citation Format: Kanako Sakaeda, Koji Kurose, Minoru Fukuda, Nanae Sugasaki, Akitoshi Kinoshita, Takashi Kitazaki, Masaaki Fukuda, Takeshi Masuda, Noboru Hattori, Yusuke Atarashi, Yumiko Sakai, Yasuhiro Irino, Mami Yamaki, Toshiyuki Sato, Hiroshi Mukae, Toru Oga, Mikio Oka. Development of automated immunoassay to detect serum biomarkers predicting response to immune checkpoint inhibitors in NSCLC [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A61.

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Background Waitlist mortality due to donor shortage for lung transplantation is a serious problem worldwide. Currently, the selection of recipients is mainly based on registration order in Japan. However, scientific evidence for risk stratification for waitlist mortality is needed in future. We hypothesized that patient-reported dyspnea and health would predict mortality in patients waitlisted for lung transplantation. Methods Using data on 203 patients who were registered as candidates for lung transplantation from deceased donors, we analyzed factors related to waitlist mortality. Dyspnea was evaluated by the modified Medical Research Council (mMRC) dyspnea scale and health status was measured with the St. George’s Respiratory Questionnaire (SGRQ). Results Among 197 patients who met inclusion criteria, the main underlying disease was interstitial pneumonia (IP) in 99 patients. During the median follow-up period of 572 days, 72 patients on the waitlist died and 96 received lung transplantation (69 from deceased donor). Univariable competing risk analyses revealed that both mMRC dyspnea and SGRQ Total were significantly associated with waitlist mortality (p = 0.003 and p < 0.001). Multivariable competing risk analyses revealed that the mMRC and SGRQ were associated with waitlist mortality, among age, IP, arterial carbon dioxide pressure, and forced vital capacity, which were all significant factors in univariable analyses. Conclusions Both mMRC dyspnea and SGRQ were significantly associated with waitlist mortality regardless of patients’ background, underlying disease, and pulmonary function. Patient-reported dyspnea and health should be measured not only from the perspective of multi-dimensional analysis including subjective perceptions, but also as risk stratification for waitlist mortality.