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Distinctive features of tumor-infiltrating ?? T lymphocytes in human colorectal cancer.

ABSTRACT: ?? T cells usually infiltrate many different types of cancer, but it is unclear whether they inhibit or promote tumor progression. Moreover, properties of tumor-infiltrating ?? T cells and those in the corresponding normal tissue remain largely unknown. Here we have studied features of ?? T cells in colorectal cancer, normal colon tissue and peripheral blood, and correlated their levels with clinicopathologic hallmarks. Flow cytometry and transcriptome analyses showed that the tumor comprised a highly variable rate of TILs (5-90%) and 4% ?? T cells on average, with the majority expressing V?1. Most V?1 and V?2 T cells showed a predominant effector memory phenotype and had reduced production of IFN- ? which was likely due to yet unidentified inhibitory molecules present in cancer stem cell secretome. Transcriptome analyses revealed that patients containing abundant ?? T cells had significantly longer 5-year disease free survival rate, suggesting their efficacy in controlling tumor at very early stage.

SUBMITTER: Meraviglia S

PROVIDER: S-EPMC5665062 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Distinctive features of tumor-infiltrating γδ T lymphocytes in human colorectal cancer.

Meraviglia S S Lo Presti E E Tosolini M M La Mendola C C Orlando V V Todaro M M Catalano V V Stassi G G Cicero G G Vieni S S Fourniè J J JJ Dieli F F

Oncoimmunology 20170713 10

γδ T cells usually infiltrate many different types of cancer, but it is unclear whether they inhibit or promote tumor progression. Moreover, properties of tumor-infiltrating γδ T cells and those in the corresponding normal tissue remain largely unknown. Here we have studied features of γδ T cells in colorectal cancer, normal colon tissue and peripheral blood, and correlated their levels with clinicopathologic hallmarks. Flow cytometry and transcriptome analyses showed that the tumor comprised a ...[more]

PMID: 29123962

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Project description:There is a pressing need for novel immunotherapeutic targets in colorectal cancer (CRC). Cytotoxic T cell infiltration is well established as a key prognostic indicator in CRC, and it is known that these tumor infiltrating lymphocytes (TILs) target and kill tumor cells. However, the specific antigens that drive these CD8+ T cell responses have not been well characterized. Recently, phosphopeptides have emerged as strong candidates for tumor-specific antigens, as dysregulated signaling in cancer leads to increased and aberrant protein phosphorylation. Here, we identify 120 HLA-I phosphopeptides from primary CRC tumors, CRC liver metastases and CRC cell lines using mass spectrometry and assess the tumor-resident immunity against these posttranslationally modified tumor antigens. Several CRC tumor-specific phosphopeptides were presented by multiple patients' tumors in our cohort (21% to 40%), and many have previously been identified on other malignancies (58% of HLA-A*02 CRC phosphopeptides). These shared antigens derived from mitogenic signaling pathways, including p53, Wnt and MAPK, and are therefore markers of malignancy. The identification of public tumor antigens will allow for the development of broadly applicable targeted therapeutics. Through analysis of TIL cytokine responses to these phosphopeptides, we have established that they are already playing a key role in tumor-resident immunity. Multifunctional CD8+ TILs from primary and metastatic tumors recognized the HLA-I phosphopeptides presented by their originating tumor. Furthermore, TILs taken from other CRC patients' tumors targeted two of these phosphopeptides. In another cohort of CRC patients, the same HLA-I phosphopeptides induced higher peripheral T cell responses than they did in healthy donors, suggesting that these immune responses are specifically activated in CRC patients. Collectively, these results establish HLA-I phosphopeptides as targets of the tumor-resident immunity in CRC, and highlight their potential as candidates for future immunotherapeutic strategies.

Project description:BACKGROUND:We sought to investigate associations between dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) features and tumor-infiltrating lymphocytes (TILs) in breast cancer, as well as to study if MRI features are complementary to molecular markers of TILs. METHODS:In this retrospective study, we extracted 17 computational DCE-MRI features to characterize tumor and parenchyma in The Cancer Genome Atlas cohort (n?=?126). The percentage of stromal TILs was evaluated on H&E-stained histological whole-tumor sections. We first evaluated associations between individual imaging features and TILs. Multiple-hypothesis testing was corrected by the Benjamini-Hochberg method using false discovery rate (FDR). Second, we implemented LASSO (least absolute shrinkage and selection operator) and linear regression nested with tenfold cross-validation to develop an imaging signature for TILs. Next, we built a composite prediction model for TILs by combining imaging signature with molecular features. Finally, we tested the prognostic significance of the TIL model in an independent cohort (I-SPY 1; n?=?106). RESULTS:Four imaging features were significantly associated with TILs (P?<?0.05 and FDR?<?0.2), including tumor volume, cluster shade of signal enhancement ratio (SER), mean SER of tumor-surrounding background parenchymal enhancement (BPE), and proportion of BPE. Among molecular and clinicopathological factors, only cytolytic score was correlated with TILs (??=?0.51; 95% CI, 0.36-0.63; P?=?1.6E-9). An imaging signature that linearly combines five features showed correlation with TILs (??=?0.40; 95% CI, 0.24-0.54; P?=?4.2E-6). A composite model combining the imaging signature and cytolytic score improved correlation with TILs (??=?0.62; 95% CI, 0.50-0.72; P?=?9.7E-15). The composite model successfully distinguished low vs high, intermediate vs high, and low vs intermediate TIL groups, with AUCs of 0.94, 0.76, and 0.79, respectively. During validation (I-SPY 1), the predicted TILs from the imaging signature separated patients into two groups with distinct recurrence-free survival (RFS), with log-rank P?=?0.042 among triple-negative breast cancer (TNBC). The composite model further improved stratification of patients with distinct RFS (log-rank P?=?0.0008), where TNBC with no/minimal TILs had a worse prognosis. CONCLUSIONS:Specific MRI features of tumor and parenchyma are associated with TILs in breast cancer, and imaging may play an important role in the evaluation of TILs by providing key complementary information in equivocal cases or situations that are prone to sampling bias.

Dataset Information

Distinctive features of tumor-infiltrating ?? T lymphocytes in human colorectal cancer.

Publications

Distinctive features of tumor-infiltrating γδ T lymphocytes in human colorectal cancer.

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