Abstract

Background

Non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of all lung cancer cases, and is characterized by a poor response to chemotherapy and a low survival rate. Treatment targeting the immune checkpoint inhibitor pathway PD-1/PD-L1 has been found to be effective against NSCLC with manageable side effects, but with only 20-25% of patients showing a positive response there is an urgent need for additional immunotherapy options for this group of patients. LAG-3 and PD-1 are often co-expressed and upregulated on T cells leading to immune exhaustion and tumor growth, and co-blockade of the LAG-3 and PD-1 pathways has been shown to synergize to improve T cytotoxic cell responses.

Methods

In order to perform a comprehensive immunoprofiling of NSCLC tumors we used MultiOmyx™, an immunofluorescence (IF) multiplexing assay that utilize a pair of directly conjugated Cyanine dye-labeled (Cy3, Cy5) antibodies per round of staining. Using a 16-marker panel we have analyzed the proportion of B cells, T cell subtypes, M1/M2-type tumor-associated macrophages, as well as the expression of PD-1, PD-L1, LAG-3, and TIM-3 in 20 samples from patients with NSCLC.

Results

LAG-3 was found to be expressed mainly on T cytotoxic cells in both subtypes, but the overall density of LAG-3 was 59% higher in squamous cell carcinoma (SCC) tumors compared to adenocarcinoma tumors. In both SCC and adenocarcinoma subtypes TIM-3 was found primarily on tumor-associated macrophages (TAMs), followed by an equal distribution on helper and cytotoxic T cells. When analyzing the proportion of T cytotoxic cells infiltrating into the tumor area, we observed an apparent synergy between LAG-3 and PD-1, suggesting a therapeutic benefit of dual checkpoint blockade of LAG-3 and PD-1 in NSCLC.

Conclusion

It is our hope that these data will help provide new insights into the biology of NSCLC that can ultimately be used to explore novel immunotherapeutic interventions for lung cancer treatment.

Legal entity responsible for the study

NeoGenomics.

Funding

NeoGenomics.

Disclosure

A. Juncker-Jensen: Full / Part-time employment: NeoGenomics. M. Nagy: Full / Part-time employment: NeoGenomics. J. Kuo: Full / Part-time employment: NeoGenomics. E. Leones: Full / Part-time employment: NeoGenomics. F. Sahafi: Full / Part-time employment: NeoGenomics. K. Pham: Full / Part-time employment: NeoGenomics. E. Parnell: Full / Part-time employment: NeoGenomics.

中文翻译：

---

131P PD-1和LAG-3协同驱动NSCLC肿瘤中T细胞毒性细胞的肿瘤浸润

抽象的

背景

非小细胞肺癌（NSCLC）约占所有肺癌病例的80-85％，其特征是对化学疗法的反应较差且生存率较低。已经发现针对免疫检查点抑制剂途径PD-1 / PD-L1的治疗可有效治疗NSCLC，且副作用可控，但只有20-25％的患者显示阳性反应，因此迫切需要其他免疫疗法来治疗这组病人。LAG-3和PD-1通常在T细胞上共表达和上调，从而导致免疫力衰竭和肿瘤生长，并且LAG-3和PD-1途径的共阻断已显示出协同作用，可改善T细胞毒性细胞反应。

方法

为了对NSCLC肿瘤进行全面的免疫分析，我们使用MultiOmyx™，这是一种免疫荧光（IF）多重分析，每轮染色使用一对直接偶联的花青染料标记的（Cy3，Cy5）抗体。使用16个标记的面板，我们分析了B细胞，T细胞亚型，M1 / M2型肿瘤相关巨噬细胞的比例，以及PD-1，PD-L1，LAG-3和TIM-在非小细胞肺癌患者中，每20个样本中就有3个。

结果

发现LAG-3主要在两种亚型的T细胞毒性细胞上表达，但与腺癌相比，鳞状细胞癌（SCC）肿瘤中LAG-3的总体密度高59％。在SCC和腺癌亚型中，TIM-3主要在肿瘤相关的巨噬细胞（TAM）上发现，然后在辅助和细胞毒性T细胞上均等分布。当分析渗入肿瘤区域的T细胞毒性细胞的比例时，我们观察到LAG-3和PD-1之间有明显的协同作用，这表明在非小细胞肺癌中LAG-3和PD-1双重检查点阻断具有治疗优势。

结论

我们希望这些数据将有助于提供对NSCLC生物学的新见解，最终可以将其用于探索肺癌治疗的新型免疫疗法干预措施。

负责研究的法人实体

新基因组学。

资金

新基因组学。

揭露

A. Juncker-Jensen：全职/兼职：NeoGenomics。M. Nagy：全职/兼职：NeoGenomics。J. Kuo：全职/兼职：NeoGenomics。E. Leones：全职/兼职：NeoGenomics。F. Sahafi：全职/兼职：NeoGenomics。K. Pham：全职/兼职：NeoGenomics。E. Parnell：全职/兼职：NeoGenomics。