Activated tissue resident memory T-cells (CD8+CD103+CD39+) uniquely predict survival in left sided “immune-hot” colorectal cancers

Abstract

IntroductionCharacterization of the tumour immune infiltrate (notably CD8+ T-cells) has strong predictive survival value for cancer patients. Quantification of CD8 T-cells alone cannot determine antigenic experience, as not all infiltrating T-cells recognize tumour antigens. Activated tumour-specific tissue resident memory CD8 T-cells (TRM) can be defined by the co-express of CD103, CD39 and CD8. We investigated the hypothesis that the abundance and localization of TRM provides a higher-resolution route to patient stratification.MethodsA comprehensive series of 1000 colorectal cancer (CRC) were arrayed on a tissue microarray, with representative cores from three tumour locations and the adjacent normal mucosa. Using multiplex immunohistochemistry we quantified and determined the localization of TRM.ResultsAcross all patients, activated TRM were an independent predictor of survival, and superior to CD8 alone. Patients with the best survival had immune-hot tumours heavily infiltrated throughout with activated TRM. Interestingly, differences between right- and left-sided tumours were apparent. In left-sided CRC, only the presence of activated TRM (and not CD8 alone) was prognostically significant. Patients with low numbers of activated TRM cells had a poor prognosis even with high CD8 T-cell infiltration. In contrast, in right-sided CRC, high CD8 T-cell infiltration with low numbers of activated TRM was a good prognosis.ConclusionThe presence of high intra-tumoural CD8 T-cells alone is not a predictor of survival in left-sided CRC and potentially risks under treatment of patients. Measuring both high tumour-associated TRM and total CD8 T-cells in left-sided disease has the potential to minimize current under-treatment of patients. The challenge will be to design immunotherapies, for left-sided CRC patients with high CD8 T-cells and low activate TRM,that result in effective immune responses and thereby improve patient survival.

Ionizable Lipid Nanoparticle-Mediated TRAIL mRNA Delivery in the Tumor Microenvironment to Inhibit Colon Cancer Progression

“…Our study revealed that normalization of the TME resulted in enhanced frequency of CD4+ and CD8+ T cell infiltration in human colon cancer ( Figure 7A–C ), and this T cell infiltration is a significant prognostic factor in this type of cancer. 47 , 62 , 63 Combining LNP-TRAIL treatment with normalization of the TME reduced tumor volume ( Figure 5C–E ) and increased frequency of tumor cell death in humanized mice ( Figure 6A and B ). Furthermore, our results demonstrated that treatment with LNP-TRAIL combined with TME normalization increased caspase-3 ( Figure 6C and D ).…”

“…The process of tumor rejection initiates with the infiltration of immune cells, particularly T cells, into the tumor site following the initial CTL response. 47,48 Therefore, we used humanized mice to assess the infiltration of immune cells into the tumor following treatment with LNP-TRAIL combined with Los or Ang (1)(2)(3)(4)(5)(6)(7). data indicate that normalization of the TME not only enhanced the efficiency and delivery of LNP-TRAIL in the TME but also stimulated the infiltration of cytotoxic CD8+ T cells (Figure 7A-C) and inflammatory infiltrate (Figure S4A-C), which could be associated with enhanced death of tumor cells.…”

Single-cell transcriptomics and Mendelian randomization reveal LUCAT1’s role in right-sided colorectal cancer risk

“…This approach is particularly vital for revealing cellular heterogeneity in disease states, especially in complex and heterogeneous cancers such as colorectal cancer. Colorectal cancer, a prevalent malignancy, is categorized into left-sided and right-sided types, each differing significantly in molecular characteristics, clinical manifestations, and prognosis ( Choi and Kim, 2023 ; Sustic et al, 2023 ; Talhouni et al, 2023 ). For instance, left-sided colorectal cancers are commonly associated with KRAS and BRAF mutations, whereas right-sided cancers are more linked to microsatellite instability and CpG island methylation anomalies ( Bond et al, 2023 ; Kajiwara et al, 2023 ).…”

Inhomogeneously distributed ferroptosis with a high peak-to-valley ratio may improve the antitumor immune response

“…had reported that instead of been damaged by RT, a large proportion of preexisting tumor TRM CD8 T cells survive and mediate antitumor responses ( 28 ). In multi-cancer types, the abundance of TRM phenotype in tumor correlates with longer disease-free and overall survival ( 29 , 30 ). TRM cells are characterized by the expression of CD103 and CD69, which are more radio-resistant than circulating/lymphoid tissue T cells may survive in irradiated tumor.…”