Lung adenocarcinomas exhibit various patterns of genomic alterations. During the development of this cancer, KRAS serves as a driver oncogene with a relatively high mutational frequency. Emerging data suggest that lung adenocarcinomas with KRAS mutations can show enhanced PD-L1 expression and additional somatic mutations, thus linking the prospect of applying immune checkpoint blockade therapy to this disease. However, the responses of KRAS-mutant lung adenocarcinomas to this therapy are distinct, which is largely attributed to the heterogeneity in the tumoral immune milieus. Recently, it was revealed that KRAS-mutant lung adenocarcinomas simultaneously expressing either a LKB1 or TP53 mutation typically have different immune profiles of their tumours: tumours with a KRAS/TP53 co-mutation generally present with a significant upregulation of PD-L1 expression and tumoricidal T-cell accumulation, and those with a KRAS/LKB1 co-mutation are frequently negative for PD-L1 expression and have few tumoricidal immune infiltrates. In this regard, interrogating TP53 or LKB1 mutation in addition to PD-L1 expression will be promising in guiding clinical use of immune checkpoint blockade therapy for KRAS-mutant lung adenocarcinomas.

Generally, patients with pancreatic ductal adenocarcinoma, especially those with wide metastatic lesions, have a poor prognosis. Recently, a breakthrough in improving their survival has been achieved by using first-line chemotherapy, such as gemcitabine plus nab-paclitaxel or oxaliplatin plus irinotecan plus 5-fluorouracil plus calcium folinate. Unfortunately, regimens with high effectiveness are still absent in second- or later-line settings. In addition, although immunotherapy using checkpoint inhibitors definitively represents a novel method for metastatic cancers, monotherapy using checkpoint inhibitors is almost completely ineffective for pancreatic ductal adenocarcinomas largely due to the suppressive immune milieu in such tumors. Critically, the genomic alteration pattern is believed to impact cancer immune environment. Surprisingly, KRAS gene mutation is found in almost all pancreatic ductal adenocarcinomas. Moreover, KRAS mutation is indispensable for pancreatic carcinogenesis. On these bases, a relationship likely exists between this oncogene and immunosuppression in this cancer. During pancreatic carcinogenesis, KRAS mutation-driven events, such as metabolic reprogramming, cell autophagy, and persistent activation of the yes-associated protein pathway, converge to cause immune evasion. However, intriguingly, KRAS mutation can dictate a different immune environment in other types of adenocarcinoma, such as colorectal adenocarcinoma and lung adenocarcinoma. Overall, the KRAS mutation can drive an immunosuppression in pancreatic ductal adenocarcinomas or in colorectal carcinomas, but this mechanism is not true in KRAS-mutant lung adenocarcinomas, especially in the presence of TP53 inactivation. As a result, the response of these adenocarcinomas to checkpoint inhibitors will vary.

Gut commensal bacteria may have a potential in distorting the response of locally advanced rectal cancer (LARC) to neoadjuvant chemoradiotherapy (nCRT). To this end, fecal samples of 35 LARC patients were retrospectively collected during nCRT in our center. According to pathological tumor regression grade (TRG) classification system (AJCC 8.0), recruited patients were divided into Sensitive group (TRG 0 ~ 1, n = 12) and Resistant group (TRG 2 ~ 3, n = 23) after radical surgery. Fecal bacterial structures of two groups were compared after bacterial 16S rRNA sequencing. In this study, it was found that fecal bacterial structures of two groups before nCRT were significantly different, presenting a higher abundance of butyrate-producing bacteria in feces of Sensitive group, whereas a higher abundance of colorectal cancer-facilitated bacteria in feces of Resistant group. During nCRT, β-diversities of two groups were significantly decreased comparing to their baseline, but bacterial structures of two groups were remodeled differentially, presenting that unlike in Sensitive group, the bacterial structure in Resistant group was continuously evolved as nCRT-dose increased. Intriguingly, it was found that the abundance of Akkermansia.muciniphila, a critical member of probiotics, was positively correlated with tumorigenic bacteria in feces of LARC patients resistant to nCRT, but the bacterial function network analysis revealed that Akkermansia.muciniphila counteracted against tumorigenic bacteria, such as Escherichia and Bacteroides. This highlighted a potential of Akkermansia.muciniphila in improving LARC response to nCRT. Collectively, gut bacterial structure impacts the response of LARC to nCRT. In turn, nCRT will remodel gut bacterial structures among LARC patients, thus enabling their treatment responses to be inconsistent.