LAMTOR1 decreased exosomal PD-L1 to enhance immunotherapy efficacy in non-small cell lung cancer.

Great progress has been made in utilizing immune checkpoint blockade (ICB) for the treatment of non-small-cell lung cancer (NSCLC). Therapies targeting programmed cell death protein 1 (PD-1) and its ligand PD-L1, expressed on tumor cells, have demonstrated potential in improving patient survival rates. An unresolved issue involves immune suppression induced by exosomal PD-L1 within the tumor microenvironment (TME), particularly regarding CD8+ T cells. Our study unveiled the crucial involvement of LAMTOR1 in suppressing the exosomes of PD-L1 and promoting CD8+ T cell infiltration in NSCLC. Through its interaction with HRS, LAMTOR1 facilitates PD-L1 lysosomal degradation, thereby reducing exosomal PD-L1 release. Notably, the ability of LAMTOR1 to promote PD-L1 lysosomal degradation relies on a specific ubiquitination site and an HRS binding sequence. The findings suggest that employing LAMTOR1 to construct peptides could serve as a promising strategy for bolstering the efficacy of immunotherapy in NSCLC. The discovery and comprehension of how LAMTOR1 inhibits the release of exosomal PD-L1 offer insights into potential therapeutic strategies for improving immunotherapy. It is imperative to conduct further research and clinical trials to investigate the feasibility and efficacy of targeting LAMTOR1 in NSCLC treatment.

Wu B ，Huang X ，Shi X ，Jiang M ，Liu H ，Zhao L ... -  《Molecular Cancer》

Serum-derived exosomal PD-L1 expression to predict anti-PD-1 response and in patients with non-small cell lung cancer.

Shimada Y ，Matsubayashi J ，Kudo Y ，Maehara S ，Takeuchi S ，Hagiwara M ，Kakihana M ，Ohira T ，Nagao T ，Ikeda N ... -  《Scientific Reports》

Exosomal PD-L1 promotes tumor growth through immune escape in non-small cell lung cancer.

Kim DH ，Kim H ，Choi YJ ，Kim SY ，Lee JE ，Sung KJ ，Sung YH ，Pack CG ，Jung MK ，Han B ，Kim K ，Kim WS ，Nam SJ ，Choi CM ，Yun M ，Lee JC ，Rho JK ... -  《-》

PD-L1 expression and T cells infiltration in patients with uncommon EGFR-mutant non-small cell lung cancer and the response to immunotherapy.

The efficacy of immunotherapy in epidermal growth factor receptor (EGFR)-activating non-small cell lung cancer (NSCLC) is limited. However, a series of patients with uncommon EGFR alterations was reported to derive clinical benefit from PD-1 blockade. To characterize the tumor immune microenvironment, we retrospectively evaluated tumor PD-L1 expression and T cells infiltration among NSCLC patients with uncommon EGFR mutations. Immunohistochemistry was used to analyze the expression of PD-L1 and the abundance of CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs). Chi-square test and Cox proportional hazards regression were conducted to investigate the correlations between the immune microenvironment features and clinicopathological variables and survival, as well as to explore the potential of immunotherapy in this patient population. Among 600 NSCLC patients with EGFR alterations, we identified 49 (8.2 %) bearing uncommon mutations, including G719X, L861Q, S768I, and Ex20 ins. In total, 49.0 % (24/49) of these patients showed positive PD-L1 expression in tumor cells, markedly higher than the proportion in patients with classic sensitive mutations (19del and L858R, 12.2 % [67/551], P < 0.05). Furthermore, PD-L1 expression was associated with relatively short overall survival (OS; 15.2 vs 29.3 months, P = 0.006) and was identified as an independent predictor of OS (hazard ratio=2.57, 95 % confidence interval: 1.03-7.12, P = 0.045). Additionally, PD-L1 positivity was predominantly observed among tumors with CD8+ TILs infiltration (P = 0.001). Uncommon EGFR-mutant tumors had a high frequency (36.7 %) of concurrent PD-L1 expression and abundant CD8 + TILs infiltration. Moreover, this dual-positive group exhibited the most unfavorable prognosis (P = 0.023). Notably, patients with PD-L1 and CD8 dual positivity showed a favorable response to PD-1 inhibitors. High rates of concomitant PD-L1 expression and CD8 + TILs within the tumor microenvironment were observed in NSCLC patients with uncommon EGFR mutations. Further investigations are needed to confirm the therapeutic sensitivity to PD-1 blockade in this subgroup.

Chen K ，Cheng G ，Zhang F ，Zhu G ，Xu Y ，Yu X ，Huang Z ，Fan Y ... -  《-》

B7-1 and programmed cell death-ligand 1 in primary and lymph node metastasis lesions of non-small cell lung carcinoma.

Programmed cell death ligand 1 (PD-L1) status has been reported to be different between metastatic and primary lesions in some cases. Therefore, the interaction between carcinoma and immune cells could influence their expression in the tumor microenvironment. PD-L1 is known to bind not only to Programmed cell death 1 (PD-1) but also to B7-1 (CD80). In this study, we examined the interaction between lung carcinoma cell lines and peripheral blood mononuclear cells (PBMCs) in vitro. We then examined the significance of B7-1 expression non-small cell lung cancer (NSCLC) microenvironment. The interaction of lung carcinoma cell lines and PBMC through the soluble factors was analyzed using a co-culture system. The changes in expression of immune checkpoint-related factors in PBMC were examined by PD-1/PD-L1 Checkpoint Pathway qPCR Array Kit. B7-1 expression in NSCLC tissues was examined by immunohistochemistry. B7-1 was upregulated following the co-culture with the lung carcinoma cell lines. B7-1 expression in NSCLC tissues was significantly higher in smokers and squamous cell carcinomas and was significantly positively correlated with PD-L1 status in primary cancer. However, B7-1 and PD-1 were not correlated between primary and metastatic diseases in the same patients. PD-1 inhibitors inhibited PD-1/PD-L1 binding but not PD-L1/B7-1 binding. These results demonstrated that the intratumoral ratio of B7-1 positive T cells in NSCLC tissue could be involved in the therapeutic efficacy of PD-L1 inhibitors. This study focused on lymph node metastasis but other sites of distant metastases should be explored by further analysis.

Yamada T ，Miki Y ，Suzuki M ，Kondoh O ，Saito-Koyama R ，Ono K ，Okada Y ，Sasano H ... -  《Cancer Medicine》