Abstract
Simple SummaryA subset of colorectal cancers (CRCs) is characterized by a mismatch repair deficiency that is frequently associated with microsatellite instability (MSI). The compromised DNA repair machinery leads to the accumulation of tumor neoantigens affecting the sensitivity of MSI metastatic CRC to immune checkpoint inhibitors (CPIs), both upfront and in later lines of treatment. However, up to 30% of MSI CRCs exhibit primary resistance to frontline immune based therapy, and an additional subset develops acquired resistance. Here, we first discuss the clinical and molecular features of MSI CRCs and then we review how the loss of antigenicity, immunogenicity, and a hostile tumor microenvironment could influence primary and acquired resistance to CPIs. Finally, we describe strategies to improve the outcome of MSI CRC patients upon CPI treatment.Immune checkpoint inhibitors (CPIs) represent an effective therapeutic strategy for several different types of solid tumors and are remarkably effective in mismatch repair deficient (MMRd) tumors, including colorectal cancer (CRC). The prevalent view is that the elevated and dynamic neoantigen burden associated with the mutator phenotype of MMRd fosters enhanced immune surveillance of these cancers. In addition, recent findings suggest that MMRd tumors have increased cytosolic DNA, which triggers the cGAS STING pathway, leading to interferon-mediated immune response. Unfortunately, approximately 30% of MMRd CRC exhibit primary resistance to CPIs, while a substantial fraction of tumors acquires resistance after an initial benefit. Profiling of clinical samples and preclinical studies suggests that alterations in the Wnt and the JAK-STAT signaling pathways are associated with refractoriness to CPIs. Intriguingly, mutations in the antigen presentation machinery, such as loss of MHC or Beta-2 microglobulin (B2M), are implicated in initial immune evasion but do not impair response to CPIs. In this review, we outline how understanding the mechanistic basis of immune evasion and CPI resistance in MMRd CRC provides the rationale for innovative strategies to increase the subset of patients benefiting from CPIs.
Highlights
3% of MMRd/microsatellite instability (MSI) CRCs arise in the context of hereditary non-polyposis colorectal cancer (HNPCC), known as Lynch Syndrome, which is a hereditary cancer syndrome characterized by heterozygous germline mutations occurring in MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MSH6, or PMS1 homolog 2 (PMS2) [81]
We suggest that several other candidates deserve to be explored as drivers of immune evasion in MSI mCRCs
Janus Kinases (JAKs)-STAT pathway mutations are a mechanism of resistance to checkpoint inhibitors (CPIs) in cancer [231] and occur frequently in MSI tumors, limiting interferon gamma response signature expression [229]
Summary
The introduction of checkpoint inhibitors (CPIs) has radically changed therapeutic strategies used for many types of solid tumors, such as melanoma, breast, cutaneous squamous, head and neck, renal, urothelial, gynecologic, and thoracic cancers [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15]. In patients with liver metastases, surgical resection within a multidisciplinary therapeutic strategy should always be considered, as it is the only treatment that can provide the possibility of prolonged survival, or even cure [21]. 15% in early stages (I-III) and only 5% in stage IV [23,24] These two subgroups of CRC reflect two diseases with different etiologies, clinic-pathological features, and outcomes to standard cytotoxic combinations or CPIs [25]. We first describe the main molecular features of MSI mCRC, focus on genetic and non-genetic mechanisms of immune-evasion and resistance to CPIs. we provide perspectives on potential strategies aiming to prevent or overcome the occurrence of these resistance mechanisms to CPIs during clinical treatment of mCRC
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