Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer
Emilie Picard1, Chris P Verschoor1, Grace W Ma2
1Health Sciences North Research Institute, Sudbury, ON, Canada.
Abstract:
Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of CRCs exhibit microsatellite instability (MSI), a molecular indicator of defective DNA mismatch repair (MMR), but the majority are microsatellite-stable (MSS). The high tumor mutational burden (TMB) and neoantigen load in MSI tumors favors the infiltration of immune effector cells, and antitumor immune responses within these tumors are strong relative to their MSS counterparts. MSI has emerged as a major predictive marker for the efficacy of immune checkpoint blockade over the last few years and nivolumab or pembrolizumab targeting PD-1 has been approved for patients with MSI refractory or metastatic CRC. However, some MSS tumors show DNA polymerase epsilon (POLE) mutations that also confer a very high TMB and may also be heavily infiltrated by immune cells making them amenable to respond to immune checkpoint inhibitors (ICI). In this review we discuss the role of the different immune landscapes in CRC and their relationships with defined CRC genetic subtypes. We discuss potential reasons why immune checkpoint blockade has met with limited success for the majority of CRC patients, despite the finding that immune cell infiltration of primary non-metastatic tumors is a strong predictive, and prognostic factor for relapse and survival. We then consider in which ways CRC cells develop mechanisms to resist ICI. Finally, we address the latest advances in CRC vaccination and how a personalized neoantigen vaccine strategy might overcome the resistance of MSI and MSS tumors in patients for whom immune checkpoint blockade is not a treatment option.
Insights
Colorectal cancer (CRC) immunotherapy efficacy varies by genetic subtype. Microsatellite instability (MSI) tumors respond well to PD-1 blockade, while microsatellite-stable (MSS) tumors with POLE mutations may also benefit. Personalized vaccines offer future promise.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Colorectal cancer (CRC) exhibits significant genetic and molecular heterogeneity, impacting immunotherapy effectiveness.
- Microsatellite instability (MSI) is a key biomarker in CRC, indicating defective DNA mismatch repair (MMR) and predicting response to immune checkpoint blockade (ICB).
- While MSI tumors show high tumor mutational burden (TMB) and immune cell infiltration, microsatellite-stable (MSS) tumors, particularly those with POLE mutations, also present high TMB and potential for immune cell infiltration.
Purpose of the Study:
- To review the diverse immune landscapes in CRC and their correlation with distinct genetic subtypes.
- To explore reasons for limited ICB success in the majority of CRC patients.
- To discuss CRC resistance mechanisms to ICB and advances in personalized neoantigen vaccination strategies.
Main Methods:
- Review of existing literature on CRC genetics, tumor microenvironment, and immunotherapy response.
- Analysis of immune cell infiltration patterns in relation to MSI and MSS subtypes, including POLE mutations.
- Examination of mechanisms of resistance to immune checkpoint inhibitors (ICIs) in CRC.
- Assessment of current and future CRC vaccination strategies, including personalized neoantigen vaccines.
Main Results:
- MSI CRC tumors generally exhibit strong antitumor immune responses and are responsive to PD-1 inhibitors like nivolumab and pembrolizumab.
- MSS CRC tumors with POLE mutations can also have high TMB and immune infiltration, suggesting potential ICB sensitivity.
- Despite immune cell infiltration being a prognostic factor, ICB efficacy remains limited in most CRC patients due to resistance mechanisms.
- Personalized neoantigen vaccines represent a promising strategy to overcome ICB resistance in both MSI and MSS CRC.
Conclusions:
- CRC's heterogeneity necessitates tailored immunotherapy approaches based on genetic and immune profiles.
- Understanding immune evasion mechanisms is crucial for improving ICB therapy in CRC.
- Personalized neoantigen vaccines hold potential to enhance treatment outcomes for a broader range of CRC patients, including those resistant to current ICB therapies.
