It has long been recognized that cancer-associated fibroblasts (CAFs) play an important role in tumor growth-promoting, rendering cells to invade surrounding tissues through cell-to-cell interactions and secretion of different invasive molecules, as well as producing angiogenic factors for the formation of new blood vessels, all of which contribute to disease progression[21]. FAP, as an important surface marker of CAFs, has attracted more and more attention, especially after the radiopharmaceuticals targeted to FAP were recently successfully developed for tumors imaging and showed a promising prospect for treating malignant tumors [10, 22, 23]. LC may be one of the optimum tumors for FAP-targeted imaging and therapy because it was found to be one of 6 cancers presented with the highest uptake level (SUVmax >12) of [68Ga] Ga-FAPI-04, a novel FAP targeting PET tracer [10, 11]. However, so far, FAPI PET/CT imaging has mainly been performed in patients with advanced LC [11, 24, 25]. It will be of great significance to uncover whether this novel PET tracer is sensitive in diagnosing LC and which histopathological type of LC can be more beneficial from the FAPI targeted therapy. For a targeted imaging or therapy, the diagnostic and therapeutic effects largely depend on the expression of the target. Therefore, a full understanding of the expression of FAP in LC helps to guide the clinical translation of FAP-targeted imaging and therapy for this disease. Nevertheless, few papers have described the whole picture of the expression of FAP in LC.
In the present study, clinical samples from the patients with LC were analyzed for the expression of FAP using immunohistochemistry staining. It was observed in the present study that nearly all (97.3%) of the LCs had positive expression of FAP, which was significantly higher than 87.7% positive rate of [18F] F-FDG PET/CT for LC, indicating that FAP-targeted PET/CT may be a more sensitive modality for diagnosing LC. [18F] F-FDG PET/CT is a standard imaging modality recommended for diagnosing and staging LC by NCCN guidance [26, 27]. However, it is not sensitive for the detection of the low invasive tumors, such as those presented as pGGO or mGGO on CT, which usually are non-FDG avid [28]. In the present study, only 3 lesions of 12 early ADCs, which presented as pGGO and mGGO lesions on CT, were observed to be [18F] F-FDG positivity on PET/CT. On the contrary, 10 of them showed positive expression of FAP, which implied that FAP-targeted PET/CT may be a supplement to [18F] F-FDG PET/CT in diagnosing the early ADCs. A case report confirmed the potential advantage of FAPI PET/CT in imaging early LC, which reported [68Ga] Ga-FAPI-04 was highly taken by an early LC, presented as mGGO on CT, while no uptake of [18F] F-FDG was observed in the lesion [29].
It was also found for the first time that there was a great variation of FAP expression level in LCs with different histopathological types. SCC was found to have the most lesions with high FAP level, followed by ADC, LCNC and SCLC. This finding may also be useful for guiding the radionuclide (177Lu or 90Y) labeled FAP-targeted therapy. It is well known, despite the introduction of multiple new therapy for LC, the survival rate remains relatively low [2], so it is necessary to find more effective treatment for LC. Our data indicated that radionuclide labeled FAP-targeted therapy may be an expectable treatment for SCCs and ADCs, which showed high FAP expression level in 100% and 85.7% of the tumors. On the contrary, low FAP expression was found in most of the lesions of SCLC, implying radionuclide labeled FAP-targeted therapy may be not suitable for SCLC. Our result was consistent with that reported by Wei Yuchun et al, which showed lower uptake of [68Ga] Ga-FAPI-04 in SCLCs than other types of LC [30].
In the ADC tumors, on univariate analysis, our study revealed the FAP level had close relationships with the tumor grade, lesion diameter, lesion attenuation and glucose metabolism (P<0.05). High FAP level in the tumors were often accompanied by larger tumor lesions, more solid attenuation and higher glucose metabolism in ADCs, which were reported to be positively related with high tumor aggressiveness [14, 19]. Therefore, it implies that FAPI imaging may be helpful to predict tumor invasiveness. Similar result was also reported by P. Moreno-Ruiz et al [31]. However, this relationship was not identified on the multivariate analysis, so further research with larger sample size is needed to determine whether this correlation really exists.
There are some limitations to this study. First, this study was retrospective study, there may have been a certain degree of bias. Second, the included sample sizes of patients were small, especially the number of LCNC and SCLC, which may fail to reflect the whole picture of the expression of FAP in LCNC and SCLC. Lastly, no benign disease was included, which make the diagnostic specificity of FAP expression for lung cancer could not be determined.