T cell immunoglobulin and ITIM domain, as a Potential Immune Checkpoint Target for Immunotherapy of Colorectal Cancer

IUBMB Life ◽  
2021 ◽  
Author(s):  
Mehrdad Fathi ◽  
Inna Pustokhina ◽  
Sergey V. Kuznetsov ◽  
Mars Khayrullin ◽  
Mohammad Hojjat‐Farsangi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Immune Checkpoint

scholarly journals B7-H5 blockade enhances CD8+ T-cell-mediated antitumor immunity in colorectal cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jiayu Wang ◽  
Hongya Wu ◽  
Yanjun Chen ◽  
Jinghan Zhu ◽  
Linqing Sun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Inverse Correlation ◽  
Immune Checkpoint Blockade ◽  
Cell Infiltration ◽  
Tumor Immune Escape ◽  
T Cell Infiltration

AbstractNegative immune checkpoint blockade immunotherapy has shown potential for multiple malignancies including colorectal cancer (CRC). B7-H5, a novel negative immune checkpoint regulator, is highly expressed in tumor tissues and promotes tumor immune escape. However, the clinical significance of B7-H5 expression in CRC and the role of B7-H5 in the tumor microenvironment (TME) has not been fully clarified. In this study, we observed that high B7-H5 expression in CRC tissues was significantly correlated with the lymph node involvement, AJCC stage, and survival of CRC patients. A significant inverse correlation was also observed between B7-H5 expression and CD8+ T-cell infiltration in CRC tissues. Kaplan−Meier analysis showed that patients with high B7-H5 expression and low CD8+ T-cell infiltration had the worst prognosis in our cohort of CRC patients. Remarkably, both high B7-H5 expression and low CD8+ T infiltration were risk factors for overall survival. Additionally, B7-H5 blockade using a B7-H5 monoclonal antibody (B7-H5 mAb) effectively suppressed the growth of MC38 colon cancer tumors by enhancing the infiltration and Granzyme B production of CD8+ T cells. Importantly, the depletion of CD8+ T cells obviously abolished the antitumor effect of B7-H5 blockade in the MC38 tumors. In sum, our findings suggest that B7-H5 may be a valuably prognostic marker for CRC and a potential target for CRC immunotherapy.

Epigenetic regulation of immune checkpoints and T cell exhaustion markers in tumor-infiltrating T cells of colorectal cancer patients

Epigenomics ◽  
2020 ◽  
Vol 12 (21) ◽  
pp. 1871-1882
Author(s):  
Varun Sasidharan Nair ◽  
Reem Saleh ◽  
Salman M Toor ◽  
Rowaida Z Taha ◽  
Ayman A Ahmed ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Immune Checkpoint ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoints ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Histone 3 ◽  
Tumor Tissues ◽  
Colorectal Cancer Patients

Aim: To elucidate the epigenetic alterations behind the upregulation of immune checkpoints and T cell exhaustion markers in colorectal cancer (CRC) patients. Materials & methods: mRNA expressions of different immune checkpoint/exhaustion markers were analyzed by quantitative real-time reverse transcriptase PCR and epigenetic investigations were performed using bisulfite sequencing and chromatin immunoprecipitation quantitative PCR. Results: mRNA expressions of PD-1, TIM-3, CTLA-4, PD-L1 and TOX2 were significantly upregulated in CD4+ and CD8+ tumor-infiltrating lymphocytes and bulk CRC tumor tissues. Histone 3 lysine 9 trimethylation was downregulated and histone 3 lysine 4 trimethylation was upregulated in PD-L1 and TOX2 promoters in tumor tissues, suggesting that PD-L1 and TOX2 upregulation in CRC tumors could be mediated by activating histone 3 lysine 4 trimethylation. Conclusion: Epigenetic modifications in promoters of immune checkpoint and T cell exhaustion genes could induce their upregulation, and potentially implicate the use of epigenetic modifiers to enhance antitumor immunity in CRC patients.

Comprehensive immune transcriptomic subtypes of colorectal cancer for development of precision immunotherapy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15078-e15078
Author(s):  
Zhou Jing ◽  
Xueguang Guo ◽  
Jing Zhao ◽  
Xiaochen Zhao ◽  
Yuzi Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Cox Regression ◽  
Cell Dysfunction ◽  
Tumor Residue ◽  
T Cell Dysfunction ◽  
T Cell Exclusion

e15078 Background: Immune checkpoint blockades (ICBs) have been approved for colorectal cancer (CRC) with microsatellite instability high (MSI-H). However, 50% to 60% MSI-H and almost 100% microsatellite stability (MSS) CRC patients can’t benefit from ICBs treatment. How to warm these “cold tumor” for boosting response to ICBs is still a problem. We aimed to integrate the expression signatures of T cell activation, exclusion and dysfunction to generate immune microenvironment subtypes which may guide precision immunotherapy. Methods: RNA-Seq of 596 CRC patients from The Cancer Genome Atlas were analyzed. T cell activation, dysfunction and exclusion signatures were calculated from TIDE model algorithm. Unsupervised clustering was used to classify CRC into various immune subtypes. Mann Whitney U test and Kruskal test were used to compare the difference among two or more than two groups. COX regression multivariate analysis was applied to analyze the association of subtypes with overall survival (OS). Results: Compared with 543 patients with MSS, 83 patients had significantly higher expression of T cell activation related genes (including CD8A, CXCL9, CXCL10, GZMB, IFNG et al) and immune checkpoint genes (including PD-L1, PD-1, LAG3 et al.), but lower signatures scores of M2-like tumor-associated macrophage (TAM) and T cell exclusion ( all P value<0.001). Based on expression signatures of myeloid-derived suppressor cell (MDSC), cancer-associated fibroblast (CAF), M2-like TAM, cytotoxic T-lymphocytes (CTL) and PD-L1, all the patients were clustered into four subtypes. Cluster 4 was enriched by MSI-H and characterized with high T cell activation and moderate T cell dysfunction and exclusion. Comparatively, another MSI-H enriched Cluster 1 had both high CTL and T cell dysfunction which indicated that activated T cell might be escaped by tumor cell. Cluster 2 and Cluster 3 were enriched by MSS and characterized with moderate T cell activation and high T cell exclusion. In survival analysis, Cluster 4 had prolonged OS (HR [95% CI]=0.46 [0.27-0.80]) compared with Cluster 1, 2 and 3, after adjusted for age, pathological stage, tumor residue, MSI status, BRAF and PIK3CA mutations. In MSS, Cluster 4 also had better prognosis than the other three clusters (HR [95% CI]=0.38 [0.20-0.73]). Conclusions: Our findings provide evidence to guide further patient stratification in ICBs treatment. The distinct immune subtypes of CRC also paved the way of combination immunotherapy based on immune microenviroment to turn “cold tumor” into “hot tumor”.

ARID1A mutation to define an immunologically active subgroup in patients with microsatellite-stable colorectal cancer.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 215-215
Author(s):  
Amir Mehrvarz Sarshekeh ◽  
Jason Roszik ◽  
Ganiraju C. Manyam ◽  
Shailesh M. Advani ◽  
Jason Willis ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Immune Checkpoint ◽  
Cell Function ◽  
Immune Therapy ◽  
Silent Mutation ◽  
Cytotoxic T Cell ◽  
Wild Type ◽  
Frame Shift ◽  
Ifn Γ

215 Background: AT-rich interactive domain 1A (ARID1A) is a chromatin regulator mutated in human cancers, frequently resulting in truncation and loss of expression of this protein. ARID1A recruits MSH2 during DNA replication to perform mismatch-repair. ARID1A deficiency has been shown to increase mutational load and immune activation in preclinical models (Shen J, Nat Med 2018) but its role in colorectal cancer (CRC) patients (pts) is being explored. Methods: The DNA sequencing and gene expression profiling of microsatellite-stable (MSS) CRC pts were extracted from TCGA and MD Anderson Cancer Center databases. The expression levels were normalized according to the mean values of each dataset. The mutational burden and expression signatures for IFN-γ and various immune markers were compared according to the ARID1A mutational status. Results: Among 417 pts with MSS CRC, 28 pts (6.7%) had a non-silent mutation in ARID1A. Out of the 58 genes most commonly mutated in CRC, non-silent mutation in ARID1A had the strongest association with the frame-shift mutation rate in MSS cases (8-fold increase, p< .001). ARID1A mutation had also a strong correlation with the IFN-γ expression signature in MSS CRC (Δz score +1.91, p< .001) . Compared with ARID1A wild-type pts, higher expression signatures for cytotoxic T cell function, NK cells, and immune checkpoints were observed in MSS ARID1A mutated cases. ARID1A mutant cases showed higher expressions of various immune checkpoint genes (CD274, CTLA4, HAVCR2, IDO1, LAG3, PDCD1, and PDCD1LG2) compared to wild-type cases (all p < .05). All findings were observed independently in both datasets. Conclusions: In MSS CRC, ARID1A mutation is associated with a high expression of IFN-γ pathway and immune signatures (such as cytotoxic T cell function and immune checkpoint markers). The immunogenicity of ARID1A mutant cases is likely due to the increased level of neoantigens resulting from the increased rate of frame-shift mutations. Tumors with ARID1A mutation may be more susceptible to immune therapy-based treatment strategies and should likely be recognized as a unique molecular subgroup in future immune therapy trials.

scholarly journals Expression and Prognostic Significance of CD47–SIRPA Macrophage Checkpoint Molecules in Colorectal Cancer

2021 ◽  
Vol 22 (5) ◽  
pp. 2690
Author(s):  
Akane Sugimura-Nagata ◽  
Akira Koshino ◽  
Satoshi Inoue ◽  
Aya Matsuo-Nagano ◽  
Masayuki Komura ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Regulatory Protein ◽  
Prognostic Significance ◽  
Rank Test ◽  
Cd163 Expression ◽  
Anti Cancer

Despite the confirmed anti-cancer effects of T-cell immune checkpoint inhibitors, in colorectal cancer (CRC) they are only effective in a small subset of patients with microsatellite-unstable tumors. Thus, therapeutics targeting other types of CRCs or tumors refractory to T-cell checkpoint inhibitors are desired. The binding of aberrantly expressed CD47 on tumor cells to signal regulatory protein-alpha (SIRPA) on macrophages allows tumor cells to evade immune destruction. Based on these observations, drugs targeting the macrophage checkpoint have been developed with the expectation of anti-cancer effects against T-cell immune checkpoint inhibitor-refractory tumors. In the present study, 269 primary CRCs were evaluated immunohistochemically for CD47, SIRPA, CD68, and CD163 expression to assess their predictive utility and the applicability of CD47–SIRPA axis-modulating drugs. Thirty-five percent of the lesions (95/269) displayed CD47 expression on the cytomembrane of CRC cells. CRCs contained various numbers of tumor-associated immune cells (TAIs) with SIRPA, CD68, or CD163 expression. The log-rank test revealed that patients with CD47-positive CRCs had significantly worse survival than CD47-negative patients. Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio (R) = 0.23), age < 70 years (HR = 0.48), and high SIRPA-positive TAI counts (HR = 0.55) as potential favorable factors. High tumor CD47 expression (HR = 1.75), lymph node metastasis (HR = 2.26), and peritoneal metastasis (HR = 5.80) were cited as potential independent risk factors. Based on our observations, CD47–SIRPA pathway-modulating therapies may be effective in patients with CRC.

scholarly journals Tn Antigen Expression Defines an Immune Cold Subset of Mismatch-Repair Deficient Colorectal Cancer

2020 ◽  
Vol 21 (23) ◽  
pp. 9081
Author(s):  
Takuro Matsumoto ◽  
Hirokazu Okayama ◽  
Shotaro Nakajima ◽  
Katsuharu Saito ◽  
Hiroshi Nakano ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Antigen Expression ◽  
Immune Checkpoint Blockade ◽  
High Rate ◽  
Cellular Immunotherapy ◽  
Small Subset ◽  
Tn Antigen

Colorectal cancer (CRC) cells often express Tn antigen, a tumor-associated truncated immature O-glycan (GalNAcα-O-Ser/Thr) that can promote tumor progression. Immunotherapies against Tn antigen have been developed and are being evaluated in clinical trials. Tn antigen can also be considered a novel immune checkpoint that induces immunosuppressive signaling through glycan-biding lectins to lead effector T cell apoptosis. We evaluated the correlation of Tn antigen expression by immunohistochemistry with mismatch-repair (MMR) status, tumor-infiltrating lymphocytes, tumor cell PD-L1 expression, and clinicopathological characteristics in 507 CRC patients. Although 91.9% of CRCs showed negative or weak Tn antigen staining (Tn-negative/weak), we identified a small subset of CRCs (8.1%) that displayed particularly intense and diffuse distribution of Tn antigen immunoreactivity (Tn-strong) that closely related to deficient MMR (dMMR). Moreover, 40 dMMR CRCs were stratified into 24 Tn-negative/weak dMMR tumors (60.0%) exhibiting dense CD8+ lymphocyte infiltrate concomitant with a high rate of PD-L1 positivity, and 16 Tn-strong dMMR tumors (40.0%) that demonstrated CD8+ T cell exclusion and a lack of PD-L1 expression, which was comparable to those of proficient MMR. Our finding suggests that the immune cold subset of patients with Tn-strong dMMR CRC may be effectively treated with immune checkpoint blockade therapy or cellular immunotherapy targeting Tn antigen.

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