Abstract 1290: Distinct immune cell composition for lung squamous cell carcinoma (SCCA) and adenocarcinoma (ADCA)
Authors: Kargl Julia , Kim Kyoung-Hee , Busch Stephanie E. , Hanke Mark L. , Metz Heather E. , McIntosh Martin W. , Houghton A McGarry 
Published: August 2015

Lung cancer is the leading cause of cancer deaths worldwide, with ∼15% of lung cancer patients surviving for five years. Recent approaches in cancer therapy target immunosuppressive factors in the tumor microenvironment (TME) capable of derailing an effective immune response, using checkpoint inhibitors (e.g. anti-PD-1/PDL-1). Unfortunately, only ∼20% of patients benefit from these treatments and appropriate studies are of importance to determine the underlying molecular mechanisms.

Lung cancer is a heterogeneous disease classified by multiple histologic subtypes, with ADCA and SCCA representing the majority of non-small cell lung cancer (NSCLC).

To evaluate the complexity of the immune cell composition of the TME of human NSCLC we examined tumor and non-adjacent lung tissue from the same patients. Tissue specimen (n = 43) with corresponding clinicopathologic information were analyzed by flow cytometry and immunohistochemistry. Next generation sequencing for TCRs was performed to assess the TCR repertoire.

Surprisingly we found that immune cells comprise ∼80% of the tumor mass in NSCLC. Many immune cell types are significantly increased in tumor tissue, when compared to normal lung, such as CD3+ and CD4+ T-cells, as well as B-cells. Notably, CD4+ cell subtypes including Th17 and regulatory T cells (Treg), and IL-17-expressing γδ T cells are increased. In contrast, decreased presence of Th1 cells was observed in tumor tissue.

Remarkably, immune cell compositions are unique for lung ADCA and SCCA. In SCCA we observed a Treg (p&lt;0.0001) predominant signature with additional increased infiltration of PMNs (p = 0.047) and significant decreases in Th1 (p = 0.034) and Th17 cells (p = 0.035) when compared to ADCA. SCCA displays immune suppressive cell content indicated by low levels of CD8 effector memory RA cells (CD8+CCR7−CD45RA+, p = 0.0081), high expression of exhaustion markers on CD8 cells (e.g. PD-1, p = 0.089) as well as significantly more EpCAM+ cells expressing PDL-1 (p = 0.0073). Further, a more clonal TCR β-chain repertoire (p = 0.018) and higher frequency of the top 10 clones (p = 0.049) were observed in SCCA. The presence of PMNs at the sites of tumorigenesis inversely correlates with CD8+ cell content (ADCA: R2 = 0.24, p = 0.022; SCCA R2 = 0.84, p = 0.0002).

In contrast, ADCA represents a Th17 signature, revealing elevated levels of IL17-expressing CD4+ T-cells and γδ T cells. While SCCA immune cell content clusters well, immune cell composition in ADCA is very heterogeneous. Preliminary data suggest that driver-mutations in ADCA such as EGFR predict distinct immune cell composition.

These data provide evidence that the immune cell composition present within different NSCLC subtypes displays unique phenotypes and identifying the immunosuppressive factors in different subsets will be important for successful immune-based therapy.

Citation Format: Julia Kargl, Kyoung-Hee Kim, Stephanie E. Busch, Mark L. Hanke, Heather E. Metz, Martin W. McIntosh, A McGarry Houghton. Distinct immune cell composition for lung squamous cell carcinoma (SCCA) and adenocarcinoma (ADCA). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1290. doi:10.1158/1538-7445.AM2015-1290