Immunotherapy in colorectal cancer: rationale, challenges and potential

Abstract

Following initial successes in melanoma treatment, immunotherapy has rapidly become established as a major treatment modality for multiple types of solid cancers, including a subset of colorectal cancers (CRCs). Two programmed cell death 1 (PD1)-blocking antibodies, pembrolizumab and nivolumab, have shown efficacy in patients with metastatic CRC that is mismatch-repair-deficient and microsatellite instability-high (dMMR-MSI-H), and have been granted accelerated FDA approval. In contrast to most other treatments for metastatic cancer, immunotherapy achieves long-term durable remission in a subset of patients, highlighting the tremendous promise of immunotherapy in treating dMMR-MSI-H metastatic CRC. Here, we review the clinical development of immune checkpoint inhibition in CRC leading to regulatory approvals for the treatment of dMMR-MSI-H CRC. We focus on new advances in expanding the efficacy of immunotherapy to early-stage CRC and CRC that is mismatch-repair-proficient and has low microsatellite instability (pMMR-MSI-L) and discuss emerging approaches for targeting the immune microenvironment, which might complement immune checkpoint inhibition.

Fig. 1 |. Targets of currently FDA-approved immune checkpoint inhibitors.

Endogenous peptides are processed and presented on major histocompatibility complex (MHC) class I molecules on the surface of all human cells, including cancer cells. The peptide–MHC complex is recognized by T cell receptors (TCRs). The response of the T cell is fine-tuned by a range of co-inhibitory or co-stimulatory signals. The ligands CD80 and CD86 of the B7 family of membrane-bound ligands can bind to the co-stimulatory CD28 and, especially in activated T cells, to cytotoxic T lymphocyte antigen 4 (CTLA4). Similarly, membrane-bound programmed cell death 1 ligand 1 (PDL1) and programmed cell death 1 ligand 2 (PDL2) can engage programmed cell death 1 (PD1), leading to T cell anergy and/or apoptosis. Monoclonal antibodies that bind to either the inhibitory receptors on T cells or their cognate ligands on cancer cells antagonize inhibitory signalling and enable T cell activation and cytotoxic tumour cell killing. Currently, FDA-approved immune checkpoint inhibitors target CTLA4 (ipilimumab), PD1 (pembrolizumab and nivolumab) and PDL1 (atezolizumab and durvalumab). Pembrolizumab and nivolumab, as well as the combination of nivolumab and ipilimumab, are currently approved for colorectal cancer in the USA.

Fig. 2 |. The tumour microenvironment of dMMR–MSI-H and pMMR–MSI-L CRC.

Colorectal cancers (CRCs) can be grouped into subtypes by distinguishing those that are mismatch-repair-deficient (dMMR) and have high levels of microsatellite instability (MSI-H) (termed dMMR–MSI-H) and those that are mismatch-repair-proficient (pMMR) and are microsatellite-stable or have low levels of microsatellite instability (MSI-L) (pMMR–MSI-L tumours). a | dMMR–MSI-H CRC shows prominent tumour-infiltrating lymphocytes that are programmed cell death 1 (PD1)⁺, accompanied by increased levels of programmed cell death 1 ligand 1 (PDL1)⁺ immune cells that are primarily present at the tumour-stroma interface. This tumour also shows loss of β₂-microglobulin expression. pMMR–MSI-L CRC shows conventional morphology with no appreciable tumour-infiltrating lymphocytes. PD1⁺ lymphocytes in the stroma are rare, and no PDL1 labelling can be seen. This tumour has retained β₂-microglobulin expression. Tissue sections are stained with haematoxylin and eosin. Positive immunohistochemistry staining is shown in brown. b | dMMR–MSI-H and pMMR–MSI-L CRCs have distinct tumour microenvironments. dMMR–MSI-H tumour cells are characterized by a high number of genomic mutations and, consequently, present mutated peptides on their major histocompatibility complex (MHC) class I molecules. Complexes of mutant peptides with MHC class I are recognized as foreign neoantigens, triggering immune cell priming and infiltration. Tumour-associated macrophages are an important component of the tumour microenvironment, influencing tumour growth and progression. dMMR–MSI-H CRCs are characterized by high levels of CD8⁺ T cell infiltration, T helper 1 (T_H1) CD4⁺ T cell infiltration and IFNγ secretion. To evade immune-mediated killing in this T cell-inflamed microenvironment, tumour cells strongly upregulate T cell inhibitory ligands, such as CD80 and CD86 of the B7 family and PDL1, which bind co-inhibitory receptors, such as cytotoxic T lymphocyte antigen 4 (CTLA4) and PD1. Immune checkpoint inhibitors (ICIs) exploit this pre-existing inflamed microenvironment by antagonizing T cell inhibitor signalling, exposing the tumour cells to cytotoxic destruction. By contrast, pMMR–MSI-L tumours do not generate immunostimulatory neoantigens and are characterized by T cell exclusion from the tumour. They express relatively low levels of immune-inhibitory ligands. These features suggest reasons for the differential response of dMMR–MSI-H and pMMR–MSI-L CRCs to ICIs and might be suitable as predictive biomarkers for patient selection. TCR, T cell receptor.

Fig. 3 |. Targets of select immunomodulatory drugs in clinical trials for metastatic CRC.

Many drugs that modulate immune checkpoints are currently in clinic trials in patients with colorectal cancer (CRC) (TABLE 3). These agents act as antagonists of T cell inhibitory signals or agonists of T cell activating signals by targeting ligands expressed on the surface of tumour cells or antigen-presenting cells, receptors on the surface of T cells or metabolites and cytokines that serve as paracrine signalling molecules. 4-1BBL, 4-1BB ligand; CD40L, CD40 ligand; CTLA4, cytotoxic T lymphocyte antigen 4; ICOS, inducible T cell co-stimulator; ICOSL, inducible T cell co-stimulator ligand; IDO, indoleamine 2,3-dioxygenase; GITR, glucocorticoid-induced TNF receptor-related gene; GITRL, glucocorticoid-induced TNF receptor-related gene ligand; LAG3, lymphocyte activation gene 3 protein; MHC, major histocompatibility complex; OX40L, OX40 ligand; PD1, programmed cell death 1; PDL1, programmed cell death 1 ligand 1; TIGIT, T cell immunoreceptor with Ig and ITIM domains; TIM3, T cell immunoglobulin mucin receptor 3.