LAT1 (SLC7A5) expression shapes the colorectal cancer tumor immune microenvironment and independently predicts time to next treatment

Background
Expression of L-type amino acid transporter 1 (LAT1; gene symbol: SLC7A5) is enriched across several cancers and has been associated with poor prognosis and cancer progression. However, the relationship between LAT1 expression, the tumor microenvironment, and outcomes remains understudied in colorectal cancers.

Methods
The Tempus Lens platform was used to identify patients diagnosed with colorectal adenocarcinoma who received DNA (xT) and RNA (xR) sequencing (N = 25,836). RNA-sequencing data was normalized by transcripts per million (TPM) and transformed by log2(TPM + 1) with LAT1 expression stratified by tertiles. Immune cell counts were estimated with the quanTIseq algorithm. Real-world time to next treatment (rwTTNT) was defined as the time from first-line treatment initiation to initiation of the next therapy, or death within 30 days of treatment end or follow-up and was assessed using Cox proportional hazards models. Kruskal-Wallis rank sum tests and Pearson’s Chi-squared tests were used to compare variables.

Results
High LAT1 expression was significantly associated with shorter rwTTNT in CRC (HR = 1.13, 95% CI 1.02–1.26, p = 0.021). LAT1-High tumors showed significantly lower B-cell (2.90% vs. 3.26%, p < 0.001) and CD8 T-cell infiltration (0.11% vs. 0.16%, p < 0.001) relative to LAT1-Low CRC tumors. LAT1-High tumors were enriched for neutrophils (9.14% vs. 8.51%, p < 0.001) but depleted of classically immunosuppressive M2 macrophages (2.55% vs. 3.58%, p < 0.001). Several known prognostic genes were more frequently mutated in LAT1-High tumors, including TP53 (80.3% vs. 71.2%, q < 0.001) and APC (84.6% vs. 73.4%, q < 0.001). Conversely, LAT1-High tumors had a lower frequency of mutations in KRAS (45.7% vs. 49%, q < 0.001) and BRAF (9.8% vs. 11.1%, q = 0.010). In multivariable analysis adjusting for TP53, KRAS, and BRAF mutations, LAT1-High expression remained significantly associated with decreased rwTTNT (HR = 1.16, 95% CI 1.04–1.29, p = 0.007). No significant differences were observed in real-world overall survival across LAT1 expression levels.

Conclusions
LAT1 expression significantly impacts rwTTNT in CRC. This impact is likely driven by immunosuppressive shifts in the tumor microenvironment and is independent of TP53, KRAS, and BRAF mutational status. Further prospective analyses are needed to understand the mechanism of LAT1’s impact on the tumor microenvironment and may allow for immune modulation and therapeutic impact through this pathway.