Low density of FOXP3-positive T cells in normal colonic mucosa is related to the presence of beta2-microglobulin mutations in Lynch syndrome-associated colorectal cancer

Echterdiek, Fabian; Janikovits, Jonas; Staffa, Laura; Müller, Meike; Lahrmann, Bernd; Frühschütz, Monika; Hartog, Benjamin; Nelius, Nina; Benner, Axel; Tariverdian, Mirjam; Doeberitz, Magnus von Knebel; Grabe, Niels; Kloor, Matthias

doi:10.1080/2162402x.2015.1075692

Cited by 29 publications

(45 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4,5,8,18,19 Gene expression profiling further linked Lynch syndrome with genes involved in antigen processing and presentation, T cell activation, natural killer cell-mediated cytotoxicity, and apoptosis. 8,20–22 Loss of B2M in 28% of the Lynch syndrome tumors was within previous reported range of 21–30% and are likely caused by frameshift mutations in microsatellite regions of the B2M gene (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

Immunoprofiles of colorectal cancer from Lynch syndrome

et al. 2018

View full text Add to dashboard Cite

Colorectal cancers associated with Lynch syndrome are characterized by defective mismatch repair, microsatellite instability, high mutation rates, and a highly immunogenic environment. These features define a subset of cancer with a favorable prognosis and high likelihood to respond to treatment with anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) drugs. With the aim to define immune-evasive mechanisms and a potential impact hereof in colorectal cancers from Lynch syndrome versus hereditary cases with retained mismatch repair function, we immunohistochemically and transcriptionally profiled 270 tumors. Lynch syndrome-associated tumors showed an overrepresentation of tumor-infiltrating CD3, CD8 and CD68 positive cells, loss of beta-2-microglobulin (B2M) and up-regulation of PD-L1 on tumor cells. The gene expression signature of Lynch syndrome tumors was characterized by upregulation of genes related to antigen processing and presentation, apoptosis, natural killer cell-mediated cytotoxicity, and T cell activation. Tumors with loss of B2M and up-regulation of PD-L1 showed distinctive immunogenic profiles. In summary, our data demonstrate a complex tumor-host interplay where B2M loss and PD-L1 up-regulation influence immunological pathways and clinical outcome in Lynch syndrome tumors. Immunological classification may thus aid in the preselection of colorectal cancers relevant for treatment with anti-PD-1/PD-L1 therapies.

show abstract

Section: Discussionmentioning

confidence: 99%

Immunoprofiles of colorectal cancer from Lynch syndrome

et al. 2018

View full text Add to dashboard Cite

show abstract

“…In LS-associated MSI-H CRCs and adenomas, immune evasion can occur by MHC I loss as a result of β2-microglobulin mutations (a mechanism distinct from sporadic MSI-H CRCs) (88). Additionally, there is evidence of an immune-suppressive TME (increased density of FOXP3 + Tregs) in normal mucosa adjacent (but not distant) to CRC in LS patients with wild-type β2-microglobulin (89).…”

Section: Harnessing the Immune System For Cancer Preventionmentioning

confidence: 99%

Leveraging premalignant biology for immune-based cancer prevention

Spira

Disis

Schiller

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Prevention is an essential component of cancer eradication. Next-generation sequencing of cancer genomes and epigenomes has defined large numbers of driver mutations and molecular subgroups, leading to therapeutic advances. By comparison, there is a relative paucity of such knowledge in premalignant neoplasia, which inherently limits the potential to develop precision prevention strategies. Studies on the interplay between germ-line and somatic events have elucidated genetic processes underlying premalignant progression and preventive targets. Emerging data hint at the immune system's ability to intercept premalignancy and prevent cancer. Genetically engineered mouse models have identified mechanisms by which genetic drivers and other somatic alterations recruit inflammatory cells and induce changes in normal cells to create and interact with the premalignant tumor microenvironment to promote oncogenesis and immune evasion. These studies are currently limited to only a few lesion types and patients. In this Perspective, we advocate a large-scale collaborative effort to systematically map the biology of premalignancy and the surrounding cellular response. By bringing together scientists from diverse disciplines (e.g., biochemistry, omics, and computational biology; microbiology, immunology, and medical genetics; engineering, imaging, and synthetic chemistry; and implementation science), we can drive a concerted effort focused on cancer vaccines to reprogram the immune response to prevent, detect, and reject premalignancy. Lynch syndrome, clonal hematopoiesis, and cervical intraepithelial neoplasia which also serve as models for inherited syndromes, blood, and viral premalignancies, are ideal scenarios in which to launch this initiative.

show abstract

“…In principle, nonadaptive immune evasion may take alternative pathways, such as the JAK1-impairing mutation. However, this impairment of the IFN pathway has not been observed in representative models of ICI responsiveness [12].…”

Section: Overcoming Immune Evasion By Alternating Drug-based Treatmentsmentioning

confidence: 90%

“…To overcome immune evasion in the immune-priming context described, we outline an evolving therapy that avoids maintaining a fixed selection pressure by cycling the tumor through the two most common possibilities for immune evasion (Figure 1): (a) recruitment of immunosuppressive regulatory T cells (T regs ) and/or tumor-associated myeloid suppressive cells (TAMSCs) within the tumor microenvironment (TME) [11]; and (b) impairment of antigen presentation through beta2-microglobulin (B2M) mutation [12] or mutational deactivation of the JAK1/2 kinase, a signal transducer in the IFN pathway that induces expression of MHC-I [10]. There is evidence that under a suitable evolutionary substrate enabling selection and adaptation, i.e.…”

Section: Overcoming Immune Evasion By Alternating Drug-based Treatmentsmentioning

confidence: 99%

“…There is evidence that under a suitable evolutionary substrate enabling selection and adaptation, i.e. genetic instability provided by the Lynch syndrome [3], the (T reg, TAMSC)-recruiting 'adaptive' phenotype a and the antigen-presentation-deficient phenotype b are not only complementary but also in competition with each other [12]. Thus, expression levels of mutated B2M in cancer cells are anticorrelated with expression levels of the transcription factor FOXP3 in tumor-adjacent T regs that controls gene expression programs for T reg function.…”

Section: Overcoming Immune Evasion By Alternating Drug-based Treatmentsmentioning

confidence: 99%

See 1 more Smart Citation