B7-H4 and HHLA2, members of B7 family, are aberrantly expressed in EGFR mutated lung adenocarcinoma

Background: In order to find new immune targets for lung cancer with different EGFR mutant status, we describe differential expression profiles of checkpoint molecules of the new discovery B7 family member to find new immune targets for lung cancer with different EGFR statuses. Methods: We performed immunohistochemistry with antibodies of B7-H3, B7-H4, VISTA, B7-H6, HHLA2, IDO-1, PD-L1 and CD8 in lung adenocarcinoma tissues constructed from 372 cases in the discovery cohort and 231 cases in the validation set. The differential expression profiles of these indices in EGFR mutant and wild-type lung adenocarcinoma was described and compared. Results: In the discovery cohort, the median IHC scores of B7-H4 and HHLA2 for the EGFR mutant group were significantly higher than those in the wild-type group (median score [interquartile range], mutant vs. wild type: 3.250 [0-7.000] vs. 5.000 [1.000-7.000], P = 0.045 for B7-H4; 8.000 [6.000-10.500] vs. 7.000 [5.000-8.630] P = 0.003 for HHLA2). Meanwhile, the median IHC scores of IDO-1 and PD-L1 in the wild-type group were significantly higher than those in the mutant group (median score [interquartile range], mutant vs. wild type: 1.000 [0-5.000] vs. 3.000 [0-8.500], P = 0.000 for IDO-1; 0 [0-3.500] vs. 3.000 [0-6.000], P = 0.000 for PD-L1). Results above was confirmed in the discovery cohort. The increased CD8 and decreased HHLA2 expression levels were associated with long disease-free survival in lung adenocarcinoma (P = 0.000 for CD8 expression and P = 0.004 for HHLA2 expression). Conclusions: B7-H4 and HHLA2 are promising immune targets for lung adenocarcinoma, especially for patients with EGFR mutation.