Immunogenicity of somatic mutations in human gastrointestinal cancers

By E. Tran, M. Ahmadzadeh, Yong-Chen Lu, A. Gros, S. Turcotte, P. Robbins, J. Gartner, Zhili Zheng, Yong F Li, Satyajit Ray and 3 more. Science, 2015

702 citations recorded by the source corpus.

Low mutation rate okay for T cells Cancers that tend to have high numbers of mutations, such as melanoma and smoking-induced lung cancer, respond well to immunotherapies, whereas those with fewer mutations, such as pancreatic cancer, do not. Tran et al. searched for tumor mutation–reactive T cells in 10 patients with metastatic gastrointestinal cancers, which have relatively low mutation burdens, and discovered that 9 out of 10 harbored such cells. T cells from one patient recognized a mutation common to many types of cancers. Engineering T cells to express this particular mutation-reactive T cell receptor may extend adoptive cell immunotherapy to a larger pool of patients than previously anticipated. Science, this issue p. 1387 Individuals with cancers that have low mutation frequencies often harbor mutation-reactive T cells. It is unknown whether the human immune system frequently mounts a T cell response against mutations expressed by common epithelial cancers. Using a next-generation sequencing approach combined with high-throughput immunologic screening, we demonstrated that tumor-infiltrating lymphocytes (TILs) from 9 out of 10 patients with metastatic gastrointestinal cancers contained CD4+ and/or CD8+ T cells that recognized one to three neo-epitopes derived from somatic mutations expressed by the patient’s own tumor. There were no immunogenic epitopes shared between these patients. However, we identified in one patient a human leukocyte antigen–C*08:02–restricted T cell receptor from CD8+ TILs that targeted the KRASG12D hotspot driver mutation found in many human cancers. Thus, a high frequency of patients with common gastrointestinal cancers harbor immunogenic mutations that can potentially be exploited for the development of highly personalized immunotherapies.

Subfields: Cancer Research, Oncology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/2a0e218758c8ca8a2eba1db681d5dbbda81a43e2

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Citations in the corpus

TCRmodel: high resolution modeling of T cell receptors from sequence (2018, background): “Many studies have generated sets of TCR sequences, representing tumor-infiltrating T cells targeting neoantigens (6), and large-scale studies of TCR sequences targeting viruses and bacterial pathogens (7–9).”
Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors. (2016, neutral): “…Galluzzi et al., 2015; Sandel et al., 2005), by existing neoantigens or high mutational load allowing high-avidity TCR engagement and proliferation (Tran et al., 2015), and by an appropriate ‘‘immunogenic milieu’’ in which DAMPs can be released (e.g., the mimicking of viral infection and…”
Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition (2021, positive): “Indeed, we obtained functional data from melanoma/gastric cancer patient tumor-infiltrating lymphocyte (TIL) samples, which were screened for reactivity against neoantigen peptides (Chudley et al., 2014; Gros et al., 2016; Tran et al., 2015), and found that T cell reactive epitopes had a significant”
Genomic features of response to combination immunotherapy in patients with advanced non-small cell lung cancer (2018, background): “Several pre-clinical and clinical reports have described neoantigen-specific T cell responses that direct anti-tumor immunity (Gubin et al., 2014; Hadrup et al., 2009; McGranahan et al., 2016; Tran et al., 2015; van Rooij et al., 2013).”
Neoantigens: promising targets for cancer therapy (2023, background): “Even though no common immunogenic epitopes are shared in these patients, a prevalent hotspot driver mutation KRAS-G12D in numerous patients can be targeted by CD8 TILs.(271) Similarly, in patients with metastatic colorectal cancer, KRAS-G12D mutant-targeted CD8 TILs induce an efficient anti-tumor im”