Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy

Angelova, Mihaela; Charoentong, Pornpimol; Hackl, Hubert; Fischer, M.; Snajder, René; Krogsdam, Anne; Waldner, Maximilian J.; Bindea, Gabriela; Mlecnik, Bernhard; Galon, Jérôme; Trajanoski, Zlatko

doi:10.1186/s13059-015-0620-6

Cited by 436 publications

(468 citation statements)

References 73 publications

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“…It was based on the prediction of candidate neoepitopes by computer algorithms, as in other earlier reports (39)(40)(41)(42). Antigen presentation as reflected in the values of A-neo/HLA-A or ABC-neo/b 2 M correlated with better prognosis of ccRCC patients, although B-neo/HLA-B and Cneo/HLA-C did not.…”

Section: Discussionmentioning

confidence: 99%

“…Future studies need to determine whether in silico-predicted neoantigens do indeed induce T-cell responses in ccRCC patients and whether these are different among HLA types. At any rate, the integrated analysis of genetic and immunologic landscape using NGS technologies becomes the main stream for the development of effective cancer immunotherapies (41,42).…”

Section: Discussionmentioning

confidence: 99%

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Neoantigen Load, Antigen Presentation Machinery, and Immune Signatures Determine Prognosis in Clear Cell Renal Cell Carcinoma

Matsushita

Sato

Karasaki

et al. 2016

Cancer Immunology Research

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Tumors commonly harbor multiple genetic alterations, some of which initiate tumorigenesis. Among these, some tumorspecific somatic mutations resulting in mutated protein have the potential to induce antitumor immune responses. To examine the relevance of the latter to immune responses in the tumor and to patient outcomes, we used datasets of wholeexome and RNA sequencing from 97 clear cell renal cell carcinoma (ccRCC) patients to identify neoepitopes predicted to be presented by each patient's autologous HLA molecules. We found that the number of nonsilent or missense mutations did not correlate with patient prognosis. However, combining the number of HLA-restricted neoepitopes with the cell surface expression of HLA or b 2 -microglobulin (b 2 M) revealed that an A-neo hi /HLA-A hi or ABC-neo hi /b 2 M hi phenotype correlated with better clinical outcomes. Higher expression of immune-

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neoantigen Load, Antigen Presentation Machinery, and Immune Signatures Determine Prognosis in Clear Cell Renal Cell Carcinoma

Matsushita

Sato

Karasaki

et al. 2016

Cancer Immunology Research

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“…Our observation of high divergence between PBMC and TIL repertoires in LGG and some GBM provides evidence of tumor-associated T-cell responses in glioma. This overall approach may offer new insight into the coevolution of antitumor reactivity with tumor progression (41) independent and synergistically with gene expression-based immune profiling (45).…”

Section: Discussionmentioning

confidence: 99%

Diversity and divergence of the glioma-infiltrating T-cell receptor repertoire

Sims

Grinshpun

Feng

et al. 2016

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

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Although immune signaling has emerged as a defining feature of the glioma microenvironment, how the underlying structure of the glioma-infiltrating T-cell population differs from that of the blood from which it originates has been difficult to measure directly in patients. High-throughput sequencing of T-cell receptor (TCR) repertoires (TCRseq) provides a population-wide statistical description of how T cells respond to disease. We have defined immunophenotypes of whole repertoires based on TCRseq of the α-and β-chains from glioma tissue, nonneoplastic brain tissue, and peripheral blood from patients. Using information theory, we partitioned the diversity of these TCR repertoires into that from the distribution of VJ cassette combinations and diversity due to VJ-independent factors, such as selection due to antigen binding. Tumor-infiltrating lymphocytes (TILs) possessed higher VJ-independent diversity than nonneoplastic tissue, stratifying patients according to tumor grade. We found that the VJ-independent components of tumor-associated repertoires diverge more from their corresponding peripheral repertoires than T-cell populations in nonneoplastic brain tissue, particularly for low-grade gliomas. Finally, we identified a "signature" set of TCRs whose use in peripheral blood is associated with patients exhibiting low TIL divergence and is depleted in patients with highly divergent TIL repertoires. This signature is detectable in peripheral blood, and therefore accessible noninvasively. We anticipate that these immunophenotypes will be foundational to monitoring and predicting response to antiglioma vaccines and immunotherapy.T-cell receptor | immunoprofiling | glioma | glioblastoma | immunooncology T he potential for immunotherapy to alleviate progression and recurrence in glioma has inspired intense study of the immunological phenotypes underlying the regulation and selection of tissue-infiltrating lymphocytes (TILs). Motivated by the prospect of targeted therapy, previous studies of glioma have undertaken large-scale genomic and gene expression analysis. These studies revealed distinct phenotypic states or subtypes that stratify gliomas and resemble different glial lineages (1-3). Although immunological gene expression classifications have been associated with clinical outcomes and prognosis (4, 5), precision immunotherapy will ultimately rely on manipulation of the T-cell population that infiltrates gliomas and its underlying repertoire of T-cell receptors (TCRs). However, the structure and intertumoral heterogeneity of the TIL population in gliomas has not been described. Here, we use whole repertoire sequencing of TCRs from glioma tissue and matched peripheral blood to discover novel immunological phenotypes with implications for noninvasive patient monitoring.Local antitumor potential is, in part, a function of the TCR repertoire expressed by T cells that surveil the CNS beyond the bloodbrain barrier. Through somatic V(D)J recombination including random nucleotide insertion in each T-cell, the α-and β-cha...

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“…16 These immune checkpoint-related proteins such as PD-1 and PD-L1 have recently been found to be overexpressed in the tumor microenvironment of microsatellite unstable colorectal carcinomas collectively. 12,17 However, data regarding differences in the tumor immune microenvironment among varying histologic subtypes of microsatellite unstable colorectal carcinomas is limited. Given that medullary carcinoma represents a distinct histologic subtype with a paradoxically favorable clinical outcome, we decided to take a more comprehensive look at the microenvironment of medullary carcinoma and compare it with that seen in poorly differentiated, and both microsatellite unstable well-differentiated and microsatellite stable well-differentiated colorectal carcinomas.…”

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confidence: 99%

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment

Friedman

Brodsky

et al. 2016

Modern Pathology

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Medullary carcinoma of the colon is a unique histologic subtype of microsatellite unstable colorectal carcinoma but little is known regarding its tumor-immunoregulatory microenvironment. The aims of this study were to characterize the immune environment of medullary carcinoma and compare it with other microsatellite unstable and microsatellite stable colorectal carcinomas. An initial gene expression microarray analysis of six cases of medullary carcinoma was used to detect potentially differentially expressed genes. We extended this analysis utilizing genomic data from the Cancer Genome Atlas to compare eight cases of medullary carcinoma with other microsatellite unstable and stable carcinomas. Finally, we evaluated expression of key immune pathway proteins and lymphocyte subsets via immunohistochemistry of a large group of medullary carcinomas (n = 105) and compared these findings with three other groups: poorly differentiated, microsatellite unstable well-differentiated and microsatellite stable well-differentiated carcinomas. Microarray and the Cancer Genome Atlas data analysis identified significant upregulation of several immunoregulatory genes induced by IFNγ including IDO-1, WARS (tRNA(trp)), GBP1, GBP4, GBP5, PDCD1 (PD-1), and CD274 (PD-L1) in medullary carcinoma compared with other microsatellite unstable and microsatellite stable tumors. By immunohistochemistry, IDO-1 was expressed in 64% of medullary carcinomas compared with 19% (9/47) of poorly differentiated carcinomas, 14% (3/22) of microsatellite unstable, and 7% (2/30) of the microsatellite stable well-differentiated carcinomas (Po 0.0001). tRNA(trp) was overexpressed in 81% (84/104) of medullary carcinomas, 19% (9/47) of poorly differentiated, 32% (7/22) of microsatellite unstable, and 3% (1/30) of microsatellite stable well-differentiated carcinomas (Po 0.0001). Medullary carcinoma had higher mean CD8+ and PD-L1+ tumor-infiltrating lymphocytes compared with all other groups (P o0.0001). This study demonstrates overexpression of several immunoregulatory genes in microsatellite unstable colorectal carcinomas and that expression of these genes and proteins is more prevalent in the medullary carcinoma subtype, which may be of use both diagnostically and therapeutically.

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Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy

Cited by 436 publications

References 73 publications

Neoantigen Load, Antigen Presentation Machinery, and Immune Signatures Determine Prognosis in Clear Cell Renal Cell Carcinoma

Neoantigen Load, Antigen Presentation Machinery, and Immune Signatures Determine Prognosis in Clear Cell Renal Cell Carcinoma

Diversity and divergence of the glioma-infiltrating T-cell receptor repertoire

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment

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