Colorectal cancer (CRC) cells often express Tn antigen, a tumor-associated truncated immature O-glycan (GalNAcα-O-Ser/Thr) that can promote tumor progression. Immunotherapies against Tn antigen have been developed and are being evaluated in clinical trials. Tn antigen can also be considered a novel immune checkpoint that induces immunosuppressive signaling through glycan-biding lectins to lead effector T cell apoptosis. We evaluated the correlation of Tn antigen expression by immunohistochemistry with mismatch-repair (MMR) status, tumor-infiltrating lymphocytes, tumor cell PD-L1 expression, and clinicopathological characteristics in 507 CRC patients. Although 91.9% of CRCs showed negative or weak Tn antigen staining (Tn-negative/weak), we identified a small subset of CRCs (8.1%) that displayed particularly intense and diffuse distribution of Tn antigen immunoreactivity (Tn-strong) that closely related to deficient MMR (dMMR). Moreover, 40 dMMR CRCs were stratified into 24 Tn-negative/weak dMMR tumors (60.0%) exhibiting dense CD8+ lymphocyte infiltrate concomitant with a high rate of PD-L1 positivity, and 16 Tn-strong dMMR tumors (40.0%) that demonstrated CD8+ T cell exclusion and a lack of PD-L1 expression, which was comparable to those of proficient MMR. Our finding suggests that the immune cold subset of patients with Tn-strong dMMR CRC may be effectively treated with immune checkpoint blockade therapy or cellular immunotherapy targeting Tn antigen.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a crucial role in activating immune cells in the tumor microenvironment, thereby contributing to a more favorable response to immune checkpoint inhibitors (ICI) in colorectal cancer (CRC). However, the impact of the expression of cGAS-STING in tumor cells on the infiltration of CD8⁺ T cells and clinical outcomes in mismatch repair proficient/microsatellite stable (pMMR/MSS) CRC remains largely unknown. Our findings reveal that 56.8% of all pMMR CRC cases were cGAS-negative/STING-negative expressions (cGAS⁻/STING⁻) in tumor cells, whereas only 9.9% of all pMMR CRC showed cGAS-positive/STING-positive expression (cGAS⁺/STING⁺) in tumor cells. The frequency of cGAS⁺/STING⁺ cases was reduced in the advanced stages of pMMR/MSS CRC, and histone methylation might be involved in the down-regulation of STING expression in tumor cells. Since the expression level of cGAS-STING in tumor cells has been associated with the infiltration of CD8⁺ and/or CD4⁺ T cells and the frequency of recurrence in pMMR/MSS CRC, decreased expression of cGAS-STING in tumor cells might lead to poor immune cell infiltration and worse prognosis in most pMMR/MSS CRC patients. Our current findings provide a novel insight for the treatment of patients with pMMR/MSS CRC.

Systemic inflammation has been reported to be associated with cancer progression and metastasis. Systemic inflammation score (SIS), calculated from preoperative serum albumin level and lymphocyte-to-monocyte ratio, has been shown to be a novel prognostic factor for several types of tumors. This study aimed to evaluate the prognostic value of the SIS in patients with pT2–4 resectable gastric cancer (GC). Total 97 patients with pT2–4 GC who underwent curative surgery from 322 cases between 2009 and 2015 in Fukushima Medical University Hospital were included. We performed univariate and multivariate analyses to evaluate the usefulness of preoperative SIS and other prognostic factors for relapse-free survival (RFS) and overall survival (OS). The higher SIS score was associated with undifferentiated cancer and recurrence. Univariate analysis of RFS identified deeper tumor invasion and higher SIS were significant risk factors and multivariate analysis revealed that both of them were independent prognostic factors for RFS. As for OS, age, tumor invasion, SIS and LNR were significantly correlated with RFS. In multivariate analysis, tumor invasion, SIS and LNR were independent prognostic factors for OS. SIS was an independent prognostic factor for RFS and OS in pT2–4 resectable gastric cancer patients who underwent curative gastrectomy.

Background: KRAS mutations are detected in ~40% of colorectal cancer (CRC), yet their prognostic value is heterogeneous across specific substitutions; the impact of uncommon variants, particularly in non-metastatic disease, remains uncertain. Methods: We evaluated the prognostic role of the relatively infrequent KRAS G12A substitution in two independent retrospective cohorts of stage II–III CRC treated with surgical resection without neoadjuvant therapy: an institutional series (FMU; n = 299) and a public dataset (AC-ICAM; n = 178). Tumors were genotyped for KRAS (and BRAF in AC-ICAM), and relapse-free survival (RFS) and overall survival (OS) were investigated. Results: KRAS G12A comprised 3.0% (FMU) and 3.4% (AC-ICAM). Across genotypes, G12A showed the highest univariable hazards compared to wild-type (WT) references for both RFS and OS in each cohort. Notably, RFS events among G12A clustered within 12 months of surgery. In multivariable Cox models, G12A remained independently associated with worse RFS and OS in each cohort, whereas non-G12A KRAS mutations did not differ significantly from the WT references. Conclusions: Across two cohorts, KRAS G12A identified a small but clinically meaningful high-risk subset of stage II–III CRC characterized by early recurrence and inferior survival. Recognition of this variant may inform postoperative risk stratification in the adjuvant setting.

（症例1）76歳，男性．前立腺癌に対しホルモン療法で治療中，造影CTで胃小彎側に胃壁との境界を有する内部不均一な腫瘤を認めた．FDG-PET/CTでSUVmax 3.7のFDG集積を認めた．同時に直腸S状部に内視鏡的に切除困難な腺腫を認めたため，同時手術方針となった．腫瘍は60mm大で左胃動脈より栄養されていたが胃壁との連続性はなく完全に摘出され，小網原発GISTと診断した．（症例2）65歳，女性．人間ドックでCA19-9の高値を指摘された．造影CTで胃体部腹側に，不整形で内部不均一な巨大腫瘤を認め，FDG-PETでSUVmax 4.9のFDG集積を認めた．EUS-FNAでc-kitが弱陽性，CD34が陽性のGISTの診断であり，腫瘍径が大きいため，開腹による腫瘍摘出術を施行した．腫瘍は150mm大，小網に局在し胃や大網と癒着していたが連続性は認めず，小網原発GISTと診断した．損傷なく完全摘出し得た．いずれの症例も高リスクの小網GISTの診断であったが，術後補助化学療法は希望により施行せず，それぞれ術後31カ月，109カ月再発なく経過している．