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Harnessing the innate immune system and local immunological microenvironment to treat colorectal cancer.

ABSTRACT: Significant progress in the development of new immunotherapies has led to successful clinical trials for malignant melanoma and non-small cell lung cancer; however, for the majority of solid tumours of the gastrointestinal tract, little or no progress has been seen. The efficacy of immunotherapies is limited by the complexities of a diverse set of immune cells, and interactions between the tumour cells and all other cells in the local microenvironment of solid tumours. A large fraction of immune cells present in and around solid tumours derive from the innate arm of the immune system and using these cells against tumours offers an alternative immunotherapeutic option, especially as current strategies largely harness the adaptive arm of the immune system. This option is currently being investigated and attempts at using the innate immune system for gastrointestinal cancers are showing initial results. Several important factors, including cytokines, chemotherapeutics and the microbiome, influence the plasticity and functionality of innate (myeloid) cells in the microenvironment, and this complexity of regulation has limited translation into successful trials so far. In this review, current concepts of the immunobiology of the innate arm in the tumour microenvironment are presented in the context of clinical translation.

SUBMITTER: Kather JN

PROVIDER: S-EPMC6734657 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:OPINION STATEMENT:Managing patients with metastatic pancreatic adenocarcinoma (mPDA) is a challenging proposition for any treating oncologist. Although the potency of first-line therapies has improved with the approvals of FOLFIRINOX and gemcitabine plus nab-paclitaxel, many patients are unable to derive significant benefit from later lines of therapy upon progression. Enrollment on clinical trials remains among the best options for patients with mPDA in all lines of therapy. At our institution, we routinely check for microsatellite instability (MSI-H) and perform next-generation sequencing (NGS) at the time of diagnosis in all good performance status mPDA patients. Although MSI-H status is only found in 1% of patients with mPDA, given pembrolizumab's tissue-agnostic approval for MSI-H tumors in later-line settings, it is a viable option when deciding on subsequent lines of therapy. Any use of immune therapy in mPDA is investigational outside the MSI-H setting. NGS can identify BRCA or other DNA damage response (DDR) defects in patients which can predict sensitivity to platinum-based therapies and influence choice of both initial and later lines of therapy. It can also identify rare actionable genomic alterations such as HER2 (2%) and TRK fusions (0.1%) and offer patients the option of enrollment on clinical trials with agents targeting these or other identified alterations. We believe enrolling mPDA patients on clinical trials with immune-modulating agents is critical to determine if there are other patient subsets, outside of the MSI-H setting, who would benefit from these approaches. Immunotherapy's general tolerability and potential to generate durable responses make it particularly appealing for mPDA patients. Although single-modality immunotherapy such as checkpoint inhibitors or vaccines have not demonstrated efficacy in this disease, combinatorial strategies targeting unique aspects of PDA including the tumor microenvironment and desmoplastic stroma have shown preclinical or early-phase success. Validating these treatments with later-phase prospective studies is essential to making immunotherapy a routine component of the treatment armamentarium for mPDA patients.

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Harnessing the innate immune system and local immunological microenvironment to treat colorectal cancer.

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