146P - Biomarkers and intrinsic/acquired resistance mechanisms for atezolizumab plus chemoradiotherapy in MSS locally advanced rectal cancer: An exploratory analysis of a single center, phase II study

Background

PD-1/PD-L1 blockades with chemoradiotherapy as neoadjuvant therapy putatively benefited patients with microsatellite stable (MSS) locally advanced rectal cancer. While microenvironmental characteristics in MSS rectal cancer that closely related to the response to PD-L1 blockades with chemoradiotherapy were largely unknown.

Methods

This phase II, open-labeled, study evaluated the efficacy and safety of adding Atezolizumab to neoadjuvant chemoradiotherapy in MSS locally advanced rectal cancer. Patients with locally advanced rectal cancer (LARC) with the distance from distal border of tumor to anal verge ≤10 cm were recruited. All patients received long-course radiotherapy plus capecitabine followed by three 21-day cycles Atezolizumab and TME surgery. Bulk RNA sequencing was performed on pre-treatment biopsies and surgical resection samples.

Results

12 patients were recruited with 100% R0 resection. 50% (n=6) of MPR rate was observed, 3 of these patients achieved pCR. In pre-treatment tissues, IFN-γ pathway, MHC-II complexes and M1-macrophage, CD1B⁺, CCL19⁺ dendritic cells were significantly enriched in MPR patients. Further, increased effector memory CD4⁺ T, follicular helper T cells, and cytotoxic CD8⁺ T cells were also found in MPR patients. Interestingly, more high endothelial venules (HEVs) were discovered in MSS rectal cancer with MPR. In patients with non-MPR, reactive oxygen species (ROS), PI3K-AKT pathways were elevated. In addition, more IL1β expression together with infiltrated CXCL8⁺IL1β⁺ neutrophils were observed. Post-treatment, non-MPR tissues had higher CD39, CD103, and overexpressed CD73 from endothelial cells, suggesting adenosine-mediated resistance.

Conclusions

The study concludes that pre-treatment microenvironment correlates with therapeutic efficacy and innate resistance in MSS rectal cancer. Adenosine induced immune escape may contribute to acquired resistance. These mechanisms might be targeted to boost Atezolizumab and chemoradiotherapy's effectiveness in MSS rectal cancers.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

J. Xu.

Funding

Has not received any funding.

Disclosure

C. Zhu: Financial Interests, Personal, Leadership Role, stock-ownership: Amoy Diagnostics. X. Li, Q. Li, X. Zhang: Financial Interests, Personal, Full or part-time Employment: Amoy Diagnostics. All other authors have declared no conflicts of interest.