Independent transcriptional patterns reveal biological processes associated with disease-free survival in early colorectal cancer.

BACKGROUND: Bulk transcriptional profiles of early colorectal cancer (CRC) can fail to detect biological processes associated with disease-free survival (DFS) if the transcriptional patterns are subtle and/or obscured by other processes' patterns. Consensus-independent component analysis (c-ICA) can dissect such transcriptomes into statistically independent transcriptional components (TCs), capturing both pronounced and subtle biological processes. METHODS: In this study we (1) integrated transcriptomes (n = 4228) from multiple early CRC studies, (2) performed c-ICA to define the TC landscape within this integrated data set, 3) determined the biological processes captured by these TCs, (4) performed Cox regression to identify DFS-associated TCs, (5) performed random survival forest (RSF) analyses with activity of DFS-associated TCs as classifiers to identify subgroups of patients, and 6) performed a sensitivity analysis to determine the robustness of our results RESULTS: We identify 191 TCs, 43 of which are associated with DFS, revealing transcriptional diversity among DFS-associated biological processes. A prominent example is the epithelial-mesenchymal transition (EMT), for which we identify an association with nine independent DFS-associated TCs, each with coordinated upregulation or downregulation of various sets of genes. CONCLUSIONS: This finding indicates that early CRC may have nine distinct routes to achieve EMT, each requiring a specific peri-operative treatment strategy. Finally, we stratify patients into DFS patient subgroups with distinct transcriptional patterns associated with stage 2 and stage 3 CRC.

While treatments for patients with colorectal cancer have improved, many patients (around 30-50%) have cancers that will eventually relapse and these patients will die due to their disease. Researchers have been studying the genes involved in colorectal cancer to help us understand why some cancers might relapse. However, current methods to do this may miss subtle or hidden patterns in the gene activity related to cancer relapse. To deal with this, we used a special method called consensus-independent component analysis (c-ICA) to dig more deeply into the activity of genes. This helped us to uncover some potential biological processes underpinning colorectal cancer relapse, which ultimately could help researchers to identify better treatments for patients with colorectal cancer.

The gut wall's potential as a partner for precision oncology in immune checkpoint treatment.

The gut wall is the largest immune organ and forms a barrier through which gut microbiota interact with the immune system in the rest of the body. Gut microbiota composition plays a role in the strength and timing of the anticancer immune response on immune checkpoint inhibitors (ICI). Surprisingly, the effects of gut wall characteristics, such as physical barrier integrity, permeability, and activity and composition of the intestinal immune system, on response to ICI has received little attention. Here, we provide an overview of markers to characterize the gut wall and interventions that can modulate these gut wall characteristics. Finally, we present a future perspective on how these gut wall markers and interventions might be utilized and studied to improve ICI treatment strategies.

Immune checkpoint inhibitor treatment induces colitis with heavy infiltration of CD8 + T cells and an infiltration pattern that resembles ulcerative colitis.

Colitis is a common, but poorly understood, adverse event of immune checkpoint inhibitors that are standard-of-care for an expanding range of cancer types. This explorative study aimed to describe the immune infiltrates in the colon from individuals developing checkpoint inhibitor colitis and compare them to well-known immunophenotypes of acute graft-versus-host disease, ulcerative colitis, and Crohn's disease. Colon biopsies (n = 20 per group) of patients with checkpoint inhibitor colitis, acute graft-versus-host disease, ulcerative colitis and Crohn's disease, all colitis treatment-naïve, and of individuals with a normal colon were analyzed using immunohistochemistry: CD8 for cytotoxic T cells, CD4 for T helper cells, and CD68 to identify cells of macrophage lineage. CD8 + T cell, CD4 + T cell, and CD68 + cell counts were performed. Cell infiltration was scored as scattered/patchy or band-like in the superficial and deep gut mucosa. Checkpoint inhibitor colitis was found to be heavily infiltrated by CD8 + T cells. Comparative analysis between groups showed that both CD8 + T cell counts (P < 0.01) and immune cell infiltration patterns in checkpoint inhibitor colitis were most similar to those observed in ulcerative colitis, with a deep band-like CD4 + T cell infiltration pattern and a superficial band-like CD68 + cell infiltration pattern in both. In conclusion, this is the first immunohistopathological study comparing infiltrate characteristics of checkpoint inhibitor colitis, acute graft-versus-host disease, ulcerative colitis, and Crohn's disease. Checkpoint inhibitor colitis samples are heterogeneous, heavily infiltrated by CD8 + T cells, and show an immune cell infiltration pattern that is more similar to ulcerative colitis than to colonic acute graft-versus-host disease or colonic Crohn's disease.