The tumor microenvironment (TME) represents a significant barrier to creating effective therapies for metastatic colorectal cancer (mCRC). In several malignancies, bone marrow derived CCR2⁺ inflammatory monocytes (IM) are recruited to the TME by neoplastic cells, where they become immunosuppressive tumor associated macrophages (TAM). Here we report that mCRC expression of the chemokine CCL2 facilitates recruitment of CCR2⁺ IM from the bone marrow to the peripheral blood. Immune monitoring of circulating monocytes in patients with mCRC found this influx was a prognostic biomarker and correlated with worse clinical outcomes. At the metastatic site, mCRC liver tumors were heavily infiltrated by TAM, which displayed a robust ability to dampen endogenous anti-tumor lymphocyte activity. Using a murine model of mCRC that recapitulates these findings from human disease, we show that targeting CCR2 reduces TAM accumulation in liver metastasis and restores anti-tumor immunity. Additional quantitative analysis of hepatic metastatic tumor burden and treatment efficacy found that administration of a small molecule CCR2 inhibitor (CCR2i) improves chemotherapeutic responses and increases overall survival in mice with mCRC liver tumors. Our study suggests that targeting the CCL2/CCR2 chemokine axis decreases TAM at the metastatic site, disrupting the immunosuppressive TME and rendering mCRC susceptible to anti-tumor T-cell responses.

Colorectal cancer (CRC) is the most common gastrointestinal malignancy in the U.S.A. and approximately 50% of patients develop metastatic disease (mCRC). Despite our understanding of long non-coding RNAs (lncRNAs) in primary colon cancer, their role in mCRC and treatment resistance remains poorly characterized. Therefore, through transcriptome sequencing of normal, primary, and distant mCRC tissues we find 148 differentially expressed RNAs Associated with Metastasis (RAMS). We prioritizeRAMS11due to its association with poor disease-free survival and promotion of aggressive phenotypes in vitro and in vivo. A FDA-approved drug high-throughput viability assay shows that elevatedRAMS11expression increases resistance to topoisomerase inhibitors. Subsequent experiments demonstrateRAMS11-dependent recruitment of Chromobox protein 4 (CBX4) transcriptionally activates Topoisomerase II alpha (TOP2α). Overall, recent clinical trials using topoisomerase inhibitors coupled with our findings ofRAMS11-dependent regulation of TOP2α supports the potential use ofRAMS11as a biomarker and therapeutic target for mCRC.

Sepsis is characterized as life-threatening organ dysfunction caused by a dysregulated host immune response to infection. The purpose of this investigation was to determine the differential effect of sepsis on innate versus adaptive immunity, in humans, by examining RNA expression in specific immune cell subsets, including monocytes/macrophages and CD4 and CD8 T cells. A second aim was to determine immunosuppressive mechanisms operative in sepsis that might be amenable to immunotherapy. Finally, we examined RNA expression in peripheral cells from critically ill nonseptic patients and from cancer patients to compare the unique immune response in these disorders with that occurring in sepsis. Monocytes, CD4 T cells, and CD8 T cells from septic patients, critically ill nonseptic patients, patients with metastatic colon cancer, and healthy controls were analyzed by RNA sequencing. Sepsis induced a marked phenotypic shift toward downregulation of multiple immune response pathways in monocytes suggesting that impaired innate immunity may be fundamental to the immunosuppression that characterizes the disorder. In the sepsis cohort, there was a much more pronounced effect on gene transcription in CD4 T cells than in CD8 T cells. Potential mediators of sepsis-induced immunosuppression included Arg-1, SOCS-1, and SOCS-3, which were highly upregulated in multiple cell types. Multiple negative costimulatory molecules, including TIGIT, Lag-3, PD-1, and CTLA-4, were also highly upregulated in sepsis. Although cancer had much more profound effects on gene transcription in CD8 T cells, common immunosuppressive mechanisms were present in all disorders, suggesting that immunoadjuvant therapies that are effective in one disease may also be efficacious in the others. Key Points Sepsis induces transcription of suppressive genes in innate and adaptive immune cells. Sepsis, trauma, and cancer share many common immunosuppressive mechanisms. Monocytic transcriptomic changes during sepsis are markedly suppressive.

Sarcomas are a heterogeneous group of neoplasms that develop from bone and soft tissue. Approximately 80% of sarcomas affect soft tissue, with liposarcoma being one of the most common types, accounting for approximately 13–20% of all soft-tissue sarcomas. Per the World Health Organization, liposarcoma can be broadly classified into four different subtypes based on histologic examination: well-differentiated liposarcoma (WDLS)/atypical lipomatous tumors (ALT), dedifferentiated liposarcoma (DDLS), myxoid liposarcoma (MLS), and pleomorphic liposarcoma (PLS). WDLS/ALT is the most common liposarcoma subtype, accounting for approximately 31–33% of liposarcomas; DDLS accounts for 20%; MLS accounts for 19%; and PLS, the least common subtype, represents 7–8% of liposarcomas. Sarcoma diagnosis is challenging because of its rarity, intrinsic complexity, and diagnostic technological complexity. Sarcomas are misdiagnosed in approximately 30% of cases, leading to delays in diagnosis and access to appropriate therapy and clinical trials. Furthermore, treatment options are limited for those diagnosed with liposarcoma. This review discusses the epidemiology, pathology, and treatment options currently available for liposarcoma.

Background/Objectives: The prognostic associations of tumor genomics and metastatic patterns remain incompletely defined in leiomyosarcoma (LMS). We investigated the association between tumor mutations, sites of metastasis, and survival in patients with LMS. Methods: This single-center retrospective cohort study evaluated 110 patients with biopsy-proven LMS who underwent genomic testing between January 2009 and May 2023. Associations between tumor mutations, metastatic sites, and uterine vs. non-uterine LMS were assessed using χ² or Fisher’s exact test. Progression-free survival/recurrence-free survival (PFS/RFS) and overall survival (OS) were estimated with the Kaplan–Meier method and compared using the log-rank test, and subsequent Cox proportional hazards regression examined associations of OS and PFS/RFS with tumor mutations and metastatic sites. Results: The study included 110 subjects (F/M: 81/29; median age, 57 years; 25/110 with metastatic disease). Overall, the most common mutations were in TP53 (74/110, 67%) and RB1 (24/110, 22%), and the most common metastatic sites were the lungs (79/99, 80%) and liver (37/99, 37%). In terms of metastatic patterns, peritoneal (24/50, 48%), pelvic (23/50, 46%), and pleural (9/50, 18%) metastases were more common in the uLMS group (p = 0.001, 0.01, and 0.04, respectively), whereas liver (27/60, 45%) and retroperitoneal (15/60, 25%) metastases were more common in the nuLMS group (p = 0.03 and 0.04, respectively). ATRX mutations (17/110, 15%) and pleural metastases (11/99, 11%) were independently associated with lower OS. Predictive survival models were generated, demonstrating variable interdependent associations between genomic alterations, metastatic sites, and outcomes (OS and PFS/RFS). Post hoc analysis of an independent cohort (N = 2606) demonstrated that ATRX mutations were similarly associated with lower OS (28.95 vs. 33.86 months; p = 0.006). Conclusions: Our study identifies differences in metastatic patterns between uterine and non-uterine LMS and highlights the adverse prognostic association of ATRX mutations and pleural metastases in a leiomyosarcoma-specific cohort.

Multidisciplinary tumor boards (MTBs) facilitate decision-making among subspecialists in the care of oncology patients, but the mechanisms by which they enhance outcomes remain incompletely understood. Our aim was to measure the agreement between sarcoma MTBs and radiology reports’ disease assessment and management recommendations. This single-center IRB-approved retrospective study evaluated cases presented at a weekly sarcoma MTB from 1 August 2020 to 31 July 2021. Cases without clinical notes, imaging studies, or radiology reports were excluded. The data collected included the patient’s clinical status at the time of the MTB, the treatment response assessment by the MTB and radiologists (stable disease; partial response; complete response; progressive disease/recurrence), and the recommendations of the radiology reports and of the MTB. The agreement between the initial radiologist review and MTB on disease assessment and recommendations was analyzed using kappa statistics. In total, 283 cases met the inclusion criteria. Radiology reports provided recommendations in 34.3% of cases, which were adhered to by the ordering providers in 73.2% of cases. The agreement between MTBs and radiology reports was moderate in disease assessment (86.2% agreement; κ = 0.78; p < 0.0001) and negligible in recommendations (36% agreement; κ = 0.18; p < 0.0001). Radiologists were more likely to assign progressive disease/recurrence than MTBs (54.4% vs. 44.4%; p < 0.001) and to recommend short-term imaging follow-up more commonly than MTBs (46.4% vs. 21.7%; p < 0.001). At a tertiary care center, radiologists’ isolated interpretations of imaging findings and management recommendations frequently differ from the MTB’s consensus, reflecting the value of multidisciplinary discussions incorporating the patient’s clinical status and the available treatment options into the final radiographic assessment.