Abstract 410: Interaction between CAFs and CD8+ T in non-small cell lung cancer (NSCLC) affects prognosis and efficacy of immunotherapy
Authors: Zheng Xinlong , Zeng Dongqiang , Li Pansong , Pen Wenying , Gao Xuan , Zhou Zhipeng , Bai Jing , Li Junhui , Ding Jianming , Wang Deqiang , Zheng Suya , Lin Gen 
Published: September 2020

Background: Tumor infiltrating stromal cells and immune cells are the main components of the tumor microenvironment. Cancer-associated fibroblasts (CAFs) make up the bulk of cancer stroma and play a key role in tumor progression. Evidence indicates that CAFs are highly related to treatment response and prognosis. However, the effect of CAFs on immunotherapy response still remains unknown.

Methods: RNA-seq and clinical data were downloaded from TCGA and GEO. The sva package was used to remove batch effects. The ssGSEA algorithm was used to assess the level of infiltration of 24 immune cells and fibroblasts from each sample. ImmuneScore was calculated using the ESTIMATE method to characterize the degree of immune infiltration. OS and DFS were analyzed using the K-M method. GO enrichment analysis is used to identify the biological process of genes. The TIDE algorithm and subclass mapping were used to predict the clinical response to immune checkpoint blockade.

Results: We evaluated the infiltration abundance of 24 types of immune cells and fibroblasts in 1768 NSCLC samples. Positive correlation between immune infiltration and CAFs infiltration through multiple methods (immune cells, Immunescore, and clustering of immune cells) (Kruskal-Wallis and Pearson test, p &lt; 0.05) were found. There were only two types of immune cells in two cohorts are beneficial for prognosis, but the number of IMFRs (Immune cells / CAFs) that are positive correlated with prognosis is more than half of the total number of classes (log-rank test; P &lt; 0.05). Univariate cox regression analysis showed that almost all IMFRs tended to be favorable for prognosis. This phenomenon is called “CAFs-mediated immune resistance pattern (CMIRP)”. At the best cut-off point, patients with high fibroblast content had worse prognosis (log-rank test; P &lt;0.05). The prognostic performance of CD8+ T cells was not robust, but CD8+ T cells /fibroblasts (CFR) can effectively distinguish the overall survival (OS) rate of NSCLC patients [n = 1588; hazard ratio (HR), 0.66; 95% confidence interval (CI),0.56-0.78; P &lt; 0.001]. and DFS rate (n = 504; HR,0.46; 95% CI, 0.34-0.62; P &lt; 0.001). Multivariate analysis revealed that CFR was an independent prognostic biomarker for OS. Among the 33 independent TCGA cohorts, 29 cohorts showed a significant positive correlation between CD8 T cells and CAFs (Pearson test, P &lt; 0.05). High CFR was beneficial for OS (HR, 0.72,95% CI, 0.67-0.78, P &lt; 0.001). Next, we defined CFR high and CFR low groups in NSCLC, and found significant difference in OS rates between subgroups (log-rank test, P &lt; 0.0001). Differential genes analysis indicate that that CFR high samples were enriched with immune activation pathways including T cell activation, cytolysis, and Antigen presentation, while CFR low was associated with immunosuppression including activation of transforming growth factor β and epithelia-mesenchymal transition. Finally, The TIDE predicted the likelihood of immunotherapy response in all NSCLC tumors. The responders had a higher CFR (Kruskal-Wallis test, P &lt; 0.0001). The Submap algorithm suggested that the CFR high subgroup was more sensitive to PD-1 treatment (Bonferroni corrected, P &lt; 0.01).

Conclusion: The “CMIRP” we proposed shed light on a more accurate assessment of immune status. CFR is a potential marker for prognosis and predictive efficacy of immunotherapy in NSCLC.

Citation Format: Xinlong Zheng, Dongqiang Zeng, Pansong Li, Wenying Pen, Xuan Gao, Zhipeng Zhou, Jing Bai, Junhui Li, Jianming Ding, Deqiang Wang, Suya Zheng, Gen Lin. Interaction between CAFs and CD8+ T in non-small cell lung cancer (NSCLC) affects prognosis and efficacy of immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 410.