Abstract PR03: Genetic mechanisms of immune evasion in colorectal cancer
Bibliographic record
Abstract
Abstract Background: Immune checkpoint blockade has shown activity in microsatellite-instability high (MSI-H) colorectal cancers (CRCs). However, despite a very high mutational and neoantigen load among virtually all MSI-H tumors, the response rate is around 40-50%. In addition, for the majority of CRCs, which are microsatellite stable (MSS), immune checkpoint inhibitors have so far proven ineffective. Thus, to better understand the genetic drivers of immune evasion in CRC, we integrated next generation sequencing data from over 1200 tumors with transcriptional and immunohistochemical measures of immune infiltration. Methods: We molecularly characterized 1,211 colorectal cancers, including 592 tumors from The Cancer Genome Atlas with whole exome sequencing (WES) and whole transcriptome (RNAseq) data and 619 cancers from two prospective cohort studies with WES and immunohistochemical (IHC) annotations. To identify driver gene alterations and their selection pressures specific to MSI-high tumors, we developed a statistical method to identify significantly mutated microsatellite tracts and we further developed a method to identify copy neutral loss of heterozygosity (CN-LOH) events. We used an established immune-gene transcriptional signature as well as IHC stains against specific subsets of immune-infiltrating cells to identify genetic events associated with immune evasion. Results: We demonstrated that WNT-signaling and immune-related genes are significantly mutated in colorectal cancer. In MSI-H CRCs, we found biallelic antigen-presentation machinery (APM) mutations in the HLA Class I genes, B2M and TAP2, in addition to recurrent mutations in NLRC5 and RFX5, which downregulated HLA Class I expression. In all CRCs, we showed that WNT-signaling activity and APC-biallelic mutations are inversely associated with both transcriptional and IHC measures of T-cell infiltration. Specifically, nuclear CTNNB1 expression was inversely correlated with overall tumor-infiltrating lymphocytes (p = 0.027), CD8+ subset of T-cells (p = 0.0019) and CD45RO+ subset of T-cells (0.0080). Meanwhile, colorectal tumors with biallelic disruptive mutations in APC had a significantly decreased activated T-cell transcriptional signature (p = 4e-12) relative to samples with no disruptive mutations in APC. We further showed that in MSS tumors, AXIN2 (a key WNT-signaling effector) super-enhancer hypomethylation, independent of the APC mutation status, was further associated with decreased T-cell activity. Conclusions: In this largest CRC genomic analysis to date, we identify genetic events that are associated with immune evasion in this disease. Specifically, we find evidence of immuno-editing in MSI-H tumors through disruptive mutations in APM. In the MSS and MSI-H subtype of CRCs, we use transcriptional and immunohistochemical orthogonal analyses to demonstrate exclusion of an effective immune infiltrate in CRC through an active WNT-signaling pathway. Our results shed light on the underlying molecular mechanisms of immune exclusion in CRC and have direct implications for novel combination immunotherapy trials for patients with this disease. This abstract is also being presented as Poster B23. Citation Format: Marios Giannakis, Catherine Grasso, Daniel Wells, Tsuyoshi Hamada, Xinmeng Jasmine Mu, Michael Quist, Jonathan Nowak, Reiko Nishihara, Charles M. Connolly, Sachet Shukla, William M. Grady, David Wheeler, Catherine J. Wu, Jesse Zaretsky, Levi Garraway, Thomas Hudson, Charles Fuchs, Antoni Ribas, Riki Peters, Shuji Ogino. Genetic mechanisms of immune evasion in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr PR03.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".