744 - The decrease of TMB, TNB and HLA expression are the Mechanism of Drug Resistance of NSCLC to immunosuppressive PD-1/PD-l1.

Background

Immunotherapy, as a new treatment, has become an option after surgery, radiotherapy and chemotherapy, and its status is becoming more and more important. However, after PD-1/PD-L1 as the target of drug treatment, it is inevitable that the phenomenon of drug resistance will arise caused by the reduction of drug sensitivity. However, there is still no clear understanding of the mechanism of drug resistance to PD-1/PD-L1, which needs to be further explored.

Methods

Tissue biopsy was performed in patients with renal metastasis of lung squamous cell carcinoma, primary lung (P), renal metastases (M1), and PD-1-treated renal metastases (M2). Then, P1, M1, and M2 were sequenced by whole exome genome sequencing (WES) to construct a gene evolution map and neoantigens evolution tree. Furthermore, the genomic differences between P and M1, as well as between M1 and M2, were found, and the evolution of tumor was demonstrated.

Results

After WES, we found that 139 groups of mutations [tumor mutational burden (TMB)=4.48 mutations/MB] were detected in the most sensitive P for PD-1 treatment, and 67 neoantigens were expressed [tumor neoantigens burden (TNB)=2.16 neoantigens /MB]. Among them, 22 groups were P-specific mutations, and 9 kinds of P-specific neoantigens were expressed, among the unique neoantigens of P, 77.8% (7/9) of the neoantigens were not deleted by HLA (human leukocyte antigen). The sensitivity of patients with M1 to PD-1 was significantly lower than that of P. WES showed that a total of 201 mutations (TMB=6.48 mutation / MB) were detected in M1. Expression of 93 neoantigens (TNB=3.00 neoantigens / MB). Among them, 85 groups were M1-specific mutations, 35 kinds of M1-specific neoantigens were expressed, of which 51.4% (18/35) of the neoantigens had no deletion of HLA. M2 was resistant to PD-1, and a total of 135 mutations were detected in WES (TMB=4.35 mutation / MB), expressed 88 neoantigens (TNB=2.84 neoantigens / MB), 91 group was M1 and M2 common mutation, 43 group was M2 specific mutation. Expression of 21 kinds of M2 specific neoantigens. The HLA presenting these neoantigens was deleted.

Conclusions

The decrease of TMB, TNB and HLA expression are the important mechanisms of PD-1/PD-L1 resistance in non-small cell lung cancer.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Henan Cancer Hospital.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.