Abstract
Biological heterogeneity and low inherent immunogenicity are two features that greatly impact therapeutic management and outcome in colorectal cancer. Despite high local control rates, systemic tumor dissemination remains the main cause of treatment failure and stresses the need for new developments in combined-modality approaches. While the role of adaptive immune responses in a small subgroup of colorectal tumors with inherent immunogenicity is indisputable, the challenge remains in identifying the optimal synergy between conventional treatment modalities and immune therapy for the majority of the less immunogenic cases. In this context, cytotoxic agents such as radiation and certain chemotherapeutics can be utilized to enhance the immunogenicity of an otherwise immunologically silent disease and enable responsiveness to immune therapy. In this review, we explore the immunological characteristics of colorectal cancer, the effects that standard-of-care treatments have on the immune system, and the opportunities arising from combining immune checkpoint-blocking therapy with immune-modulating conventional treatments.
Highlights
Colorectal cancer (CRC) is the third-most commonly diagnosed cancer worldwide with 1.4 million new cases annually [1], contributing to the fourth-most common cancer-related deaths [2]
In locally advanced rectal cancer (LARC), neoadjuvant chemoradiotherapy (CRT) with a fluoropyrimidine in a non-cytotoxic radiosensitizing dose and resection of the residual tumor result in low local recurrence rates [78], but metastatic progression remains a dominant cause of failure [79,80]
We showed that circulating fms-related tyrosine kinase 3 ligand (FLT3LG) increased following neoadjuvant chemotherapy (NACT) and the sequential CRT and that the post-NACT increase was associated with favorable survival outcome
Summary
Colorectal cancer (CRC) is the third-most commonly diagnosed cancer worldwide with 1.4 million new cases annually [1], contributing to the fourth-most common cancer-related deaths [2]. Even though the majority of CRC cases are of a sporadic nature, a subgroup of patients presents with hereditary forms of CRC, such as the common manifestation of Lynch syndrome or the rare familial adenomatous polyposis In individuals with the former, inherited mutations or epigenetic inactivations of DNA mismatch-repair (MMR) genes result in a deficient MMR (dMMR) function. Immune therapies are aimed at overcoming tumor-induced immune-suppressive mechanisms and invoking antitumor immune responses This concept has proven successful in the treatment of a limited number of immunogenic tumors, but for less immunogenic cancers such as the majority of CRC cases, additional stimulation is required to breach the immune tolerance and for patients to achieve beneficial and durable treatment responses
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