2969 - Differential expression of Immune Checkpoints (PD-L1, HHLA2, B7x and B7H3) and their Association with Driver Mutations in Pulmonary Sarcomatoid Carcinoma (PSC)

Background

PSC, with epithelial (E) and sarcomatoid (S) components, is an aggressive type of non-small cell lung cancer (NSCLC). Molecularly-targeted therapy and anti-PD-1/PD-L1 immunotherapy (IO) have changed the treatment paradigm of NSCLC. The majority of PD-L1 negative NSCLC express alternative immune checkpoints (IC): B7H3, B7x and HHLA2. There is limited information on the profile of these IC and their association with driver mutations (mut) in PSC.

Methods

IC expression was examined in tissue microarrays of 41 PSC by IHC. PD-L1 positive cases were defined as PD-L1≥ 1% in tumor cells. B7X, HHLA2, and B7H3 were scored for intensity and percent staining (positive cases were intensity of 1,2 or 3). Percent of TILs was scored in 5% increments. In this cohort, 69% of patients (pts) were smokers, 20% (8 pts) had MET ex 14 skipping and 15% (6 pts) harbored KRAS mut, without cases of EGFR, BRAF or ALK fusion.

Results

PD-L1 was positive in 75% (27/36) with most (78%, 21/27) expressing PD-L1 ≥50%. Only 33% (9/27) had PD-L1 expression in both E and S components, and the expression between E and S was statistically different (P < 0.007). There was a trend of shorter overall survival in pts whose tumors were positive for PD-L1 (671 vs. 985 days). The expression of B7x, B7H3, and HHLA2 was positive in 67%, 72% and 94% of cases. All cases expressed at least one IC with 42% (15/36) being quadruple positive. 69% of cases had tumor-infiltrating lymphocyte (TIL) density≥10%. Among 8 pts with MET mut, the frequency of PD-L1, B7x, B7H3 and HHLA2 positive cases were 100% (6 with PD-L1 ≥50%), 75%, 75% and 100%. In 6 pts with KRAS mut, the rate of PD-L1, B7x, B7H3 and HHLA2 positive cases were 83% (2 with PD-L1 ≥50%), 67%, 75% and 83%. The median H-score (intensity x percent) of HHLA2 was significantly different between the METex14 vs. wildtype in both E (P = 0.0001) and S components (P = 0.01).

Conclusions

In our PSC series, PD-L1 (≥ 50%) was expressed in the majority of cases and all cases expressed at least one IC. Along with wide TIL distribution, our findings favor exploration of IO in PSC. The enrichment of METex14 and potential interplay between MET and PD-L1/HHLA2 in PSC suggest that future combination studies with MET inhibitor and IO are warranted.

Clinical trial identification

Legal entity responsible for the study

Montefiore Medical Center.

Funding

Has not received any funding.

Editorial Acknowledgement

Disclosure

X. Zang: Inventor on patent number US 9447186 B2 which covers the topic of anti-B7x cancer immunotherapy; Inventor on two pending patents which cover the topic of HHLA2-directed immunotherapy. All other authors have declared no conflicts of interest.