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. Colorectal cancer (CRC) is a major cause of cancer death worldwide. In developed countries, early detection through screening has improved the 5-year survival of patients with CRC, but ~25% of patients still present with stage 4 disease, and a further 25-50% present with early-stage disease but go on to develop metastatic disease 1-4. The prognosis for patients with metastatic CRC (mCRC) remains poor, with a median 5-year survival of only 12.5% in the USA 2. Thus, the development of more effective treatments for patients with this disease is an urgent unmet need. In the past decade, immunotherapy has elicited

Image-based consensus molecular subtype classification (imCMS) of colorectal cancer using deep learning

“…In CRC, it is well known that tumour morphology, growth pattern and architecture hold important clues to differentiating biological subtypes with clinical impact (10). The composition of the tumour microenvironment is a key component determining the tumour progression and therapy response (11,12). Tumour and non-tumour tissue contribute to image information on the histological slide and to the consensus molecular classification (CMS) of CRC at the transcriptional level (13) CMS subgrouping shows a robust association with targetable alterations and may have potential to guide treatment allocation in clinical practice (1,13).…”

MIR155HG is a prognostic biomarker and associated with immune infiltration and immune checkpoint molecules expression in multiple cancers

“…The conventional therapies, including chemotherapy and radiation therapy, remain the first‐line treatment for most cancer patients. In recent years, tumor immunotherapy has shifted from adjuvant therapy to an important treatment modality with the breakthrough of checkpoint inhibitor immunotherapy …”

“…In recent years, tumor immunotherapy has shifted from adjuvant therapy to an important treatment modality with the breakthrough of checkpoint inhibitor immunotherapy. 1 Immune checkpoint blockade treatment can give patients an unprecedented long-lasting anti-tumor response. By far the most widely used immunotherapy in various solid tumors and hematological malignancies is cytotoxic T lymphocyteassociated antigen 4 (CTLA4) or programmed cell death protein 1 (PD-1)-PD-1 ligand 1 (PD-L1) inhibitor, known as immune checkpoint inhibitors (ICIs).…”

Microsatellite instability and its associations with the clinicopathologic characteristics of diffuse large B‐cell lymphoma

“…Many cancers encode mutation‐associated neoantigens (MANAs), which might be potential determinants of immune checkpoint blockades, like PD‐1/PD‐L1 blockades . MMR‐deficient cancers have large numbers of MANAs which would stimulate the immune response . Recent studies have demonstrated that dMMR could predict the response to PD‐1 inhibitor in 12 different kinds of solid tumors, including cholangio carcinoma, endometrial cancer, neuroendocrine carcinoma, and osteosarcoma and so on .…”

“…[5][6][7] MMR-deficient cancers have large numbers of MANAs which would stimulate the immune response. 8 Recent studies have demonstrated that dMMR could predict the response to PD-1 inhibitor in 12 different kinds of solid tumors, including cholangio carcinoma, endometrial cancer, neuroendocrine carcinoma, and osteosarcoma and so on. 9 Therefore, the evaluation of MSI and MMR deficiency has significance in predicting the response to PD-1/PD-L1 checkpoint blockades in various types of cancers.…”