MSI-H/dMMR

This study clarifies the association between TRGs expression and the biological characteristics of LUAD, highlighting their potential clinical significance in molecular typing and therapeutic guidance, and laying a foundation for personalized diagnosis and treatment strategies for LUAD.

Approximately, 10-11% of patients were potentially misclassified by panels. These findings emphasize the importance of broader gene representation for accurate TMB determination near the clinical threshold-especially in tumor types lacking disease-specific ICI indications, where tissue-agnostic MSI-High/dMMR or TMB-High labeling represents the principal on-label route to ICI therapy.

Our study shows that MSI and neoantigen accumulation emerge during the evolution of precancerous lesions in LS. These findings support the clinical evaluation of Nous-209, a shared neoantigen vaccine, as an immunoprevention strategy for MSI-driven colorectal carcinogenesis, with important implications for cancer prevention research.

In this work, we adapt our mechanistic model for locally advanced MSI-H/dMMR CRC (laMCRC) to de novo metastatic MSI-H/dMMR CRC (dnmMCRC), deriving model parameters from pharmacokinetic, bioanalytical, and radiographic studies, as well as bulk RNA-sequencing data deconvolution from the TCGA COADREAD and GSE26571 datasets. We finally performed an exploratory optimisation of pembrolizumab treatment to balance efficacy, efficiency, and toxicity in dnmMCRC, comparing against currently FDA-approved regimens, analysing factors influencing treatment success and comparing immune dynamics to those in laMCRC.

Across both subtypes, aeTSAs arose predominantly from intronic translation, UTR usage, retroelement activation, and germline-like transcription, including recurrent aeTSAs from PIWIL1, L1TD1, and endogenous retroviral loci. Together, these data demonstrate that MSS CRC is not antigen poor and highlight non-canonical translation as a major, previously underappreciated contributor to the CRC immunopeptidome.

However, realizing its full potential requires addressing challenges related to tumor heterogeneity and drug resistance. Future research must focus on validating novel biomarkers and developing synergistic combination strategies to further improve patient survival.

P2, N=50, Not yet recruiting, Fred Hutchinson Cancer Center

P1, N=18, Recruiting, Thomas Jefferson University | Not yet recruiting --> Recruiting | Trial completion date: Jan 2027 --> Apr 2028 | Trial primary completion date: Jan 2027 --> Oct 2027

The revised tumor burden score (rTBS) provides a clinically actionable, cost-effective tool to enhance prognostic stratification in patients with metastatic colorectal cancer (mCRC) receiving immunotherapy. By integrating routinely available metrics (CEA, metastatic organ count, and target lesions), rTBS achieves superior prognostic discrimination (AUC = 0.768) compared to traditional biomarkers such as TMB (AUC = 0.656) and consistently stratifies outcomes across molecular subtypes. Of particular clinical relevance, rTBS identifies patients with more favorable prognosis within the MSI-L/MSS/TMB-Low subgroup, addressing a major unmet need in this biomarker-limited population. It also refines risk stratification in MSI-H/TMB-High patients by identifying those with high tumor burden and poor prognosis. By leveraging readily accessible clinical and imaging data, rTBS circumvents the need for costly molecular profiling, bringing pragmatic risk stratification within reach even in resource-constrained settings. These findings position rTBS as a useful decision-support tool for prognostic evaluation, assisting clinicians in personalizing management strategies for mCRC.

Neoadjuvant chemotherapy with docetaxel plus S-1 regimen was administered, resulting in stable disease(SD)...The patient continued adjuvant nivolumab therapy postoperatively and remained disease-free. This case highlights the potential role of perioperative immunotherapy with nivolumab in MSI-H EGJ cancers and the promise of personalized treatment strategies.

The value of this report is, therefore, not mechanistic proof but recognition of a practical morphologic-immunophenotypic observation: When a gastric carcinoma shows a sharply demarcated shift from differentiated to undifferentiated/rhabdoid morphology, dMMR should be considered, and selective ARID1A loss in the undifferentiated component may be associated with dedifferentiation. These findings should be interpreted with caution as preliminary, hypothesis-generating observations that require validation in larger studies with more extensive molecular profiling.

Consequently, molecular testing revealed mismatch repair deficiency (dMMR) among two cancers, thereby confirming the diagnosis of LS. This case suggests that UPS may represent a rare extracolonic manifestation of LS and highlights the importance of considering MMR/MSI testing in sarcomas of uncertain origin, which may have implications for diagnosis and personalized treatment strategies, including the use of immune checkpoint inhibitors.