Background: RICTOR is a critical component of the mTOR2 complex. Through activation of AKT, SGK1, PKC and other downstream pathways, the RICTOR/mTOR signaling is essential in controlling cell survival, proliferation, metabolism, migration, protein degradation and cytoskeleton functions. Moreover, our recent work implicates that RICTOR amplification may define a unique subtype of NSCLC that can potentially be targeted by mTOR1/2 inhibitors. Additionally, previous evidence also suggest that the PI3K/AKT/mTOR pathway may be involved in immune regulation.
Immunotherapy targeting PD-1/PD-L1 has significantly shifted the treatment landscape in NSCLC. PD-1/PD-L1 belongs to the B7 family of ligands and CD28 family of receptors, which play crucial roles in the regulation of T-cell responses. B7x, HHLA2 and B7-H3 are recently discovered B7 family ligands, which function as T-cell co-inhibitory molecules. These new immune checkpoints are widely expressed in NSCLC and in particular, these alternative immune checkpoints are commonly found in PD-L1 negative tumors. In the current study, we investigated the potential roles of the RICTOR/mTOR signaling on immune modulation, especially the regulation of immune checkpoints.
Results: Using multiple RICTOR amplified NSCLC cells lines (H23, H1703 and H1734), we found that knockdown of RICTOR by siRNA or inducible shRNA resulted in decreased whole lysate and cell surface PD-L1 and HHLA-2 expression but not B7x or B7-H3. RICTOR knockdown can also downregulate IFN-gamma induced PD-L1 expression. Moreover, inducible RICTOR overexpression upregulates PD-L1 levels and also modestly HHLA2 expression. Our preliminary data also indicate that this regulation is likely occurring at a post-transcriptional level. In addition to potential modulation of immune checkpoint molecules, preliminary analysis of 14,698 NSCLC cases indicate that tumors with RICTOR amplification more often have higher levels of tumor mutation burden (TMB) than other lung cancers: the mean TMB was 14.9 mut/Mb in RICTOR-amplified vs 9.2 mut/Mb in non-amplified cases. TMB is a surrogate for increased number of expressed tumor neoantigens and is an important biomarker for response to immune checkpoint inhibitors.
Conclusion: Our study provides new insight into the regulation of the tumor immune microenvironment by RICTOR/mTOR signaling. This may pave the way for designing or improving immunotherapeutic strategies in lung cancer by exploiting the novel immune escape mechanisms in these tumors.
Citation Format: Mariam Alexander, Ni Fan, Xiaoxin Ren, Jeffrey Ross, Hao Wang, Feng Wang, Balazs Halmos, Roman Perez-Soler, Xingxing Zang, Haiying Cheng. RICTOR/mTOR signaling regulates novel immune checkpoints in non-small cell lung cancer (NSCLC) [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 1017.