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We have shown that activin A (activin), a TGF-β superfamily member, has pro-metastatic effects in colorectal cancer (CRC). In lung cancer, activin activates pro-metastatic pathways to enhance tumor cell survival and migration while augmenting CD4+ to CD8+ communications to promote cytotoxicity. Here, we hypothesized that activin exerts cell-specific effects in the tumor microenvironment (TME) of CRC to promote anti-tumoral activity of immune cells and the pro-metastatic behavior of tumor cells in a cell-specific and context-dependent manner. We generated an Smad4 epithelial cell specific knockout (Smad4-/-) which was crossed with TS4-Cre mice to identify SMAD-specific changes in CRC. We also performed IHC and digital spatial profiling (DSP) of tissue microarrays (TMAs) obtained from 1055 stage II and III CRC patients in the QUASAR 2 clinical trial. We transfected the CRC cells to reduce their activin production and injected them into mice with intermittent tumor measurements to determine how cancer-derived activin alters tumor growth in vivo. In vivo, Smad4-/- mice displayed elevated colonic activin and pAKT expression and increased mortality. IHC analysis of the TMA samples revealed increased activin was required for TGF-β-associated improved outcomes in CRC. DSP analysis identified that activin co-localization in the stroma was coupled with increases in T-cell exhaustion markers, activation markers of antigen presenting cells (APCs), and effectors of the PI3K/AKT pathway. Activin-stimulated PI3K-dependent CRC transwell migration, and the in vivo loss of activin lead to smaller CRC tumors. Taken together, activin is a targetable, highly context-dependent molecule with effects on CRC growth, migration, and TME immune plasticity.

Increased tumor infiltrating lymphocytes (TIL) are associated with improved patient responses to immunotherapy. As a result, there is interest in enhancing lymphocyte trafficking particularly to colon cancers since the majority are checkpoint blockade-resistant and microsatellite stable. Here, we demonstrate that activated T-cells (ATC) armed with anti-CD3 x anti-EGFR bispecific antibody increases TIL and mediate anti-tumor cytotoxicity while decreasing tumor cell viability. Furthermore, treatment induces endogenous anti-tumor immunity that resisted tumor rechallenge and increased memory T-cell subsets in the tumor. When combined with targeted tumor expression of the tumor necrosis factor superfamily member LIGHT, activated T-cell proliferation and infiltration were further enhanced, and human colorectal tumor regressions were observed. Our data indicate that tumor-targeted armed bispecific antibody increases TIL trafficking and is a potentially potent strategy that can be paired with combination immunotherapy to battle microsatellite stable colon cancer. SIGNIFICANCE: Enhancing trafficking of tumor infiltrating lymphocytes (TILs) to solid tumors has been shown to improve outcomes. Unfortunately, few strategies have been successful in the clinical setting for solid tumors, particularly for "cold" microsatellite stable colon cancers. In order to address this gap in knowledge, this study combined TNFSF14/LIGHT immunomodulation with a bispecific antibody armed with activated T-cells targeted to the tumor. This unique T-cell trafficking strategy successfully generated anti-tumor immunity in a microsatellite stable colon cancer model, stimulated T-cell infiltration, and holds promise as a combination immunotherapy for treating advanced and metastatic colorectal cancer.

Biliary tract cancer consists of cholangiocarcinoma (CC) and gallbladder cancer (GBC). When resectable, surgery provides the best chance at long-term survival. Unfortunately, surgery for these tumors is associated with long operative times, high morbidities, and prolonged hospital stays. Minimally invasive surgery has been shown to impact selected outcomes, including length of stay, in other diseases, and robotic surgery may offer additional advantages compared to laparoscopic surgery in treating bile duct cancers. This is a systematic review of robotic surgery for biliary tract cancer. Predetermined selection criteria were used to appraise the literature. The PRISMA guidelines were followed. In total, 20 unique articles with a total of 259 patients with biliary tract cancer undergoing robotic surgery met the inclusion criteria. For CC and GBC, respectively, the weighted average operative time was 401 and 277 min, the estimated blood loss was 348 and 260 mL, the conversion rate to open was 7 and 3.5%, the all-cause morbidity was 52 and 9.7%, the major morbidity was 12 and 4.4%, the perioperative mortality was 1.4 and 0%, the length of stay was 15 and 4.8 days, the positive margin rate was 27 and 9%, and the number of lymph nodes retrieved was 4.2 and 8. Robotic surgery for biliary tract cancer appears non-inferior to open surgery when compared to the published contemporary data. However, the current literature on the topic is of low quality, and future prospective/randomized studies are needed.