Impact of KRAS mutation subtypes on morphological heterogeneity and immune landscape in surgically treated lung adenocarcinoma.

Background: Although Kirsten rat sarcoma virus (KRAS) mutations represent the most frequent oncogenic driver alterations in Caucasian lung adenocarcinoma (LADC) patients, their impact on immune phenotype and tumor morphology is largely unexplored. Here, we investigated the associations between KRAS mutation subtypes, immune landscape, and tumor heterogeneity in surgically treated LADC, with a particular focus on specific tumor growth patterns.

Methods: This study included 87 surgically treated patients with histologically confirmed early-stage LADC. Three tumorous and one non-tumorous tissue microarray (TMA) cores were collected from each patient. KRAS genotyping was performed using polymerase chain reaction (PCR)-based assays. We assessed the immune landscape by evaluating the NLRP3 inflammasome, CD3, CD163, and PD-L1 expression.

Results: The mutational landscape concerning the type of KRAS mutation was mostly homogenous across TMA cores, with KRASG12C being the most frequently detected alteration. Notably, in 19 cases, the dominant mutational subtype differed between the tumor punctures originating from the same tumor. Although KRASG12A mutation was not detected in LADC samples with a lepidic growth pattern and micropapillary LADCs lacked wild-type KRAS gene, no statistically significant association was found between the KRAS mutation subtype and LADC growth pattern. NLRP3 expression significantly correlated with CD3 and CD163 expressions (P<0.001), and elevated NLRP3 levels were characteristic of LADCs with solid growth pattern (P=0.001). Tumor samples with solid morphology expressed significantly higher levels of PD-L1 than acinar- or lepidic-pattern LADCs (P=0.007 and P=0.002, respectively).

Conclusions: KRAS mutation subtypes may have a heterogeneous distribution across different tumor regions, contributing to cases with concomitant mutation subtypes that create significant diagnostic challenges. The growth pattern-specificity of NLRP3 and PD-L1 offers additional guidance for the future development of alternative immunotherapeutic approaches.